viral neuropathies

Viral Neuropathies in the Temporal Bone

Advances in Oto-Rhino-LaryngologyVol. 60

Series Editor

W. Arnold Munich

Viral Neuropathies inthe Temporal Bone

Richard R. Gacek Mobile, Ala

Mark R. Gacek Mobile, Ala

100 figures, and 8 tables, 2002

Basel � Freiburg � Paris � London � New York �

New Delhi � Bangkok � Singapore � Tokyo � Sydney

Prof. Richard R. Gacek,Prof. Mark R. GacekDivision of Otolaryngology, Head and Neck SurgeryCollege of Medicine, University of South Alabama307 University Blvd., NHSB Suite 1600Mobile AL 36688–0002 (USA)

Library of Congress Cataloging-in-Publication Data

Gacek, Richard R.Viral neuropathies in the temporal bone / Gacek, Richard R., Gacek, Mark R.

p. ; cm. – (Advances in oto-rhino-laryngology, ISSN 0065-3071 ; v. 60)Includes bibliographical references and index.ISBN 38055729561. Temporal bone–Diseases. 2. Facial nerve–Diseases. 3. Vestibular

apparatus–Diseases. 4. Virology. I. Gacek, Mark R. II. Title. III. Series.[DNLM: 1. Temporal Bone–innervation. 2. Temporal Bone–virology. 3. Facial Nerve

Diseases–virology. 4. Vestibulocochlear Nerve Diseases–virology. WV 201 G121v2002]RF260 .G334 2002616.7�1–dc21

2002023571

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© Copyright 2002 by S. Karger AG, P.O. Box, CH–4009 Basel (Switzerland)www.karger.comPrinted in Switzerland on acid-free paper by Reinhardt Druck, BaselISSN 0065–3071ISBN 3–8055–7295–6

Contents

VII Preface

XI Acknowledgment

Chapter 1

3 The Biology of Neurotropic VirusesGacek, R.R. (Mobile)

Chapter 2

32 Neuroanatomy of the Nerves in the Temporal BoneGacek, R.R. (Mobile)

Chapter 3

32 Meatal Ganglionitis: A Pathologic Correlate in Idiopathic FacialParalysisGacek, R.R.; Gacek, M.R. (Mobile)

Chapter 4

54 Vestibular Neuronitis: A Viral NeuropathyGacek, R.R.; Gacek, M.R. (Mobile)

Chapter 5

67 Ménière’s Disease: A Form of Vestibular GanglionitisGacek, R.R.; Gacek, M.R. (Mobile)

Chapter 6

80 The Pathology of Benign Paroxysmal Positional VertigoGacek, R.R.; Gacek, M.R. (Mobile)

Chapter 7

89 A Classification of Recurrent VestibulopathyGacek, R.R.; Gacek, M.R. (Mobile)

Chapter 8

305 Efferent System Degeneration in Vestibular GanglionitisGacek, R.R. (Mobile)

Chapter 9

324 Antiviral Therapy of Vestibular GanglionitisGacek, R.R.; Gacek, M.R. (Mobile)

327 Appendix

337 Subject Index

Contents VI

Preface

A number of otologic disorders have mystified clinicians over the years.These have been referred to as ‘idiopathic’ indicating lack of a known cause.Although animal models are useful in elucidating basic physiologic mecha-nisms, recurrent neuropathies (vestibular, facial) of the temporal bone (TB) are unique to humans. Therefore, human TB specimens represent the bestsource of information providing insight into the pathology of these neuropathicdisorders.

For hundreds of years, Bell’s palsy (IFP) and Ménière’s disease (MD) havebeen regarded as idiopathic. Although displaced otoconia have been implicatedin the mechanism of benign paroxysmal positional vertigo, the precise stimulusfor degenerated otoconia has also been unknown (idiopathic). Only vestibularneuronitis was assumed to be an inflammatory disorder of the vestibular nervebecause of its clinical association with viral-type illnesses and supported byserologic evidence of elevated viral antibodies.

The description of endolymphatic hydrops (EH) in TB from patients withthe clinical symptoms of MD [1, 2] provided the impetus for a long series ofinvestigations into the concept of obstruction in longitudinal flow of endolymphto the endolymphatic sac. The theory received support from the experimentaldemonstration of EH following obstruction of the endolymphatic duct in someanimals (guinea pig, gerbil, rabbit) [3, 4]. However, failure to produce EH innonhuman primates [5] and the absence of vertigo in the successful animalmodels of EH detracted from the EH theory of MD and accounted for the equi-vocal results obtained by treatments designed to reduce endolymph.

In a similar way, the previous concept of IFP held that an ischemic eventleads to edema of the facial nerve and compression within the surrounding bonycanal. Surgical decompression to relieve intraneural pressure did not achievesuperior results compared to no treatment in a large number of consecutivepatients with IFP [6]. Molecular amplification of herpes simplex virus 1 byPCR on vestibular nerves (ganglia) from patients with MD [7] and IFP [8] sup-ports a viral role in these idiopathic disorders.

We have demonstrated in human TB specimens from patients with IFP,MD, vestibular neuronitis and benign paroxysmal positional vertigo a pattern ofdegenerative changes in the facial nerve (meatal ganglion) and vestibular nerve(and ganglion) which is similar to morphologic changes in herpes zoster of thetrigeminal nerve. This evidence has been summarized in the series of reportscontained in this volume of Advances in Otorhinolaryngology.

Harold F. Schuknecht, MD, predicted a viral cause for MD in his discussionof delayed EH, a form of MD. ‘Assuming that viral labyrinthitis can occur ininfants as a subclinical disease that results in delayed endolymphatic hydrops,we may have an explanation for the cause of Ménière’s disease. Viewed in thiscontext the disease entity known as delayed endolymphatic hydrops becomesthe missing link in understanding the pathogenesis of Ménière’s disease’ [9]. Wededicate this series of studies to the memory of H.F. Schuknecht whose life-longprofessional passion was the TB.

Armed with this concept of pathogenesis for the recurrent vestibulopathies,the variable features and unpredictable nature of the ‘three faces’ of vestibularganglionitis can be understood. An antiviral approach is warranted but willrequire substantive changes in present-day antiviral pharmaceuticals.

R.R. GacekM.R. Gacek

References

1 Hallpike CS, Cairns H: Observations on the pathology of Ménière’s syndrome. J Laryngol Otol1938;53:625–655.

2 Yamakawa K: Über die pathologische Veränderung bei einem Ménière-Kranken. J Otorhinolaryngol Soc Jpn 1938;44:2310–2312.

3 Kimura RS, Schuknecht HF: Membranous hydrops in the inner ear of the guinea pig after obliter-ation of the endolymphatic sac. Pract Otorhinolaryngol 1965;27:343–354.

4 Kimura RS: Animal models of endolymphatic hydrops. Am J Otolaryngol 1982;3:447–451.5 Swant J, Schuknecht HF: Long term effects of destruction of the endolymphatic sac in a primate

species. Laryngoscope 1988;98:1183–1189.6 Peitersen E, Andersen P: Spontaneous course of 220 peripheral non-traumatic facial palsies. Acta

Otolaryngol Suppl (Stockh) 1967;224:296–300.

Preface VIII

7 Pitovski DZ, Robinson AM, Garcia-Ibanez F, Wirt R: Presence of HSV-I gives products character-istic of active infection in the vestibular ganglia of patients diagnosed with acute Ménière’s disease(abstract 457). 22nd Annu Midwinter Res Meet Assoc Res Otolaryngol, St Petersburg Beach,February 1999.

8 Burgess RC, Michaels L, Bale JF, Smith RH: Polymerase chain reaction amplification of herpessimplex viral DNA from the geniculate ganglion of a patient with Bell’s palsy. Ann Otol RhinolLaryngol 1994;103:775–779.

9 Schuknecht HF: Pathology of the Ear, ed 2. Philadelphia, Lea & Febiger, 1993, pp 235–244.

Preface IX

Acknowledgment

The authors are grateful to L. Nan Johnson for excellent secretarial assis-tance in manuscript preparation. The professional help in medical illustrationsby Lynda Touart and Frank Vogtner is much appreciated.

Financial support for this publication was provided by Glaxo SmithklinePharmaceutical Co. and the University of South Alabama School of Medicine.

Gacek RR, Gacek MR: Viral Neuropathies in the Temporal Bone. Adv Otorhinolaryngol. Basel, Karger 2002, vol 60, pp 1–11

The Biology of Neurotropic Viruses

Richard R. Gacek

Neurotropic (NT) viruses are characterized by their affinity for neuralstructures, specifically sensory neurons. One group of NT viruses commonlyassociated with neuropathy is the �-herpes virinae subfamily [1]. This group of viruses has a propensity for invading sensory neurons, the establishment oflatency within ganglion cells and a possibility of reactivation at some later dateby a stressful stimulus. The best known members of this group of viruses are the herpes simplex (HSV) types 1 and 2, and the herpes zoster or varicella virus[2]. These viruses are responsible for the clinical syndromes of HSV labialisand herpes zoster [3]. Other members of this family of NT viruses are the cyto-megalic inclusion virus, pseudorabies and the Epstein-Barr virus [1]. Withinthese types are hundreds of strains representing mutant varieties of the virus type.

NT viruses are important clinically because of the high incidence of expo-sure to HSV in the population worldwide [4]. Exposure to the virus and the estab-lishment of latency in sensory nerves may occur in individuals as early as thefirst 10 years of life. The incidence of exposure and establishment of latency byvirus increases with age and lower socioeconomic status [5]. It is estimated thatby the age of 25 years 75% of the population has elevated antibodies to the HSVgroup, and by the age of 60 years the exposure is over 90%. Therefore, the poten-tial for latency in various sensory ganglia of the body is high. Exposure to viralorganisms in the human body is high in the soft palate, oropharynx, hypopharynx,nose and nasopharynx where viral invasion of the mucous membrane epitheliumoccurs.

Virus presence in the epithelium of the oral cavity represents an opportunityfor invasion of a sensory neuron dependent on complementary surface structuresof the virus envelope and the sensory neuron. Virus invasion of the sensory neu-ron is mediated by glycoproteins in the virus envelope. These glycoproteins havespecific and sometimes overlapping functional roles. At least 10 glycoproteinsin the HSV virus envelope play a role in virus behavior. Only glycoprotein B (gB),glycoprotein D (gD), glycoprotein H (gH) and glycoprotein L (gL) are vital to

Chapter 3

the process of infection [6–11]. The remaining 6 glycoproteins contribute insome way to virus invasion and infectivity in host cells. These glycoproteins area reflection of the genetic makeup of the viral organism and therefore confer aparticular level of infectivity for each virus strain.

Infection of a sensory neuron occurs first by virus attachment to the cellplasma membrane, followed by penetration of the virus nucleocapsid into thecell cytoplasm and nucleus [12]. This virus attachment involves different glyco-proteins in the virus envelope and receptors on the sensory cell surface. gB andgC are primarily responsible for the initial attachment phase which depends onthe combination of positively charged viral envelope glycoprotein moieties withnegatively charged heparan sulfate receptors on the cell surface [13, 14]. Theheparan sulfate proteoglycan receptors are also genetically programmed cellfeatures that permit successful attachment and infection of the neuron by a viralorganism [6]. The initial attachment process facilitates a second attachmentphase in which gD binds to a cellular receptor belonging to the tumor necrosisfactor and nerve growth factor family [15]. gD is essential for fusion of the viralenvelope to the cell membrane and finally penetration of the cell membrane bythe virus [11, 12]. It has been determined in genetic studies that gB, gD and gHare necessary for this fusion-penetration process.

Virus-binding receptors are unevenly distributed over the plasma membraneof the neuron. The adsorption of both HSV-1 and HSV-2 is efficient in mousesynaptosomal and glial cell preparations but virtually absent on neuronal cellbodies [16, 17]. Synaptosomes adsorb virus better than glial cells. Such a favor-able uptake in synapses may account for the efficiency of virus uptake by nerveterminals and transmission along multisynaptic neuronal linkages when used asa neurobiologic tracer. The lack of receptors on neuronal perikarya might beresponsible for a reduction in HSV spread from cell to cell in peripheral ganglia.However, cell-to-cell virus spread may occur as a result of virus movement acrosscell junctions between adjacent neurons or by a viral precursor rather than thefully formed virus [18].

The animal model of HSV infection in a murine sensory ganglion indicatesthat after arrival of the virus in the ganglion cell, it accumulates within the nucleusbut after a productive infection may leave the nucleus and the cytoplasm acquiringa double envelope from the nuclear and the plasma membranes [19]. Upon arrivalin the extracellular space, the virus particles are surrounded by an increased num-ber of satellite cells (SC) which incorporate the virus within the SC nucleus andcytoplasm (fig. 1). As virus particles are enveloped by the SC, they are replacedby cytoplasmic extensions of the SC which proliferate membrane in layers. Thesemembrane layers fuse into thick membranous envelopes in a whorl-like pattern(fig. 2). In this manner, the enveloping SC surround and replace the ganglion cellbody (fig. 3). The cytoplasm of the ganglion cell may become vacuolated by the

Gacek 2

infection and replaced by SC which have increased in number (fig. 4). The SCmay replace the cell perikaryon leaving nuclear remnants at the epicenter.

After the NT virus has entered the peripheral process of a sensory neuron,the virion is carried by axoplasmic transport to the ganglion cell body (fig. 1).This process has been demonstrated to require 20–24 h. Once the virus has successfully reached the cytoplasm of the ganglion cell, it may spread to adja-cent ganglion cells by several mechanisms [19]. The virus may simply leave theinfected cell and attach to membrane receptors on nearby cells with subsequentinvasion. Alternatively, the virus may move across junctions where cells are closelyattached (tight junctions, desmosomes) and thereby elude antibodies circulating

The Biology of Neurotropic Viruses 3

Stages of Herpetic Ganglionitis

Retrograde Anterograde

Satellite Cell

A

B

C

Fig. 1. A schematic summary of the major morphologic features in NT viral ganglionitis.Drawing A represents the acute inflammatory phase, while B and C illustrate degenerativephases based on the histologic features shown in figures 2 and 3.

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Fig. 2. The vestibular ganglion in a 75-year-old female with recurrent vertigo (duration20–40 min) and positional vertigo shows ganglion cells being replaced by SC (open arrows)and a collagen-like substance replacing another (solid arrow).

Fig. 3. The meatal ganglion (MG) in a 44-year-old man with a history of episodic vertigowithout hearing loss for several years (case 5, table 1, see Appendix). Several ganglion cells(arrowheads) have been replaced by a collagen-like material surrounding nuclear remnants.FN � Facial nerve; VN � vestibular nerve.

within the extracellular space [20]. Finally SC may spread the virus to nearbyganglion cells. The tendency of NT viruses to involve adjacent neurons in a gan-glionic mass results in clusters of infected ganglion cells (fig. 5). Reactivationof virus in a group of infected ganglion cells will then result in lesions (vesicles)that are tightly grouped (i.e. herpes simplex labialis, herpes zoster). Degenera-tion of a cluster of ganglion cells produces a group of degenerated axons in thenerve trunk (fig. 6).

If the virus does not leave the neuron completely after the initial infection,it may assume a latent (subviral) state within the nucleus of the cell. All the fac-tors necessary to develop latency are not known. However, a transformation in thenecessary RNA genome for establishing latency, i.e. latency-associated transcript,is an essential event [21, 22]. Once latency has been established, reactivation ofthe virus into an active or productive infection may occur following a stimulusthat is unusually stressful or traumatic, physically or chemically. The animal modelof latent HSV infection has shown adrenaline to be capable of reactivating latentHSV [23]. An additional underlying factor is host resistance; in the immuno-compromised host or in the host with a senescent immune response, the tendencyfor reactivation of a latent virus form is greater than in the young uncompromisedhost subject.


Fig. 4. The trigeminal ganglion in case 19 (table 1, see Appendix) shows vacuolatedganglion cells surrounded by SC (open arrows). The solid arrow points to lipofuchsin granulesin a ganglion cell.

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Fig. 6. Vestibular nerve from a 61-year-old female with otosclerosis who died fromovarian cancer. Two fascicles of degenerated axons (arrows) are seen in the nerve trunk.VG � Vestibular ganglion.

Fig. 5. The vestibular ganglion in case 3 (table 1, see Appendix), a 62-year-old malewith recurrent vertigo and no hearing loss, contained clusters of ganglion cells in variousphases of degeneration (arrows). Some cells are surrounded by dark SC and inflammatorycells, while others have been replaced. VN � Vestibular nerve.

The mode of virus presence in the cell is also determined by the genotypeof host neurons. Margolis et al. [24] presented evidence that two types of neurons in the mouse dorsal root ganglion allowed a different virus presencefollowing a single inoculation of virus. In one population of ganglion cells, viralprotein synthesis was high, but transcription of latency-associated transcriptswas minimal, while in a second type of neuron viral gene expression was restrictedbut latency-associated transcript synthesis was abundant. These observationssuggest that following virus uptake in a nerve, latent infection will occur in onetype of neuron and active productive infection in another type of ganglion cellwithin the same ganglion.

The SC has long been felt to be intimately related to its ganglion cell. SC support the neuron metabolically during prolonged activity. This suggestion is sup-ported by the decreased nucleic acid content in SC while neuronal nucleic acid isincreased in the superior cervical ganglion following prolonged (3-hour) stimula-tion [25, 26]. The role of SC in the NT viral infection of a ganglion may representa response to increased neural activity as well as the need to limit the spread ofvirions released from ganglion cells. The increased density associated with mem-brane proliferation may be responsible for the collagen layers found in the onionbulb pattern observed in some types of neuronal degeneration (fig. 2, 3) [27].

The number of SC associated with normal ganglion cells varies in differentcranial nerves. This variation may be dependant on the embryologic origin ofthe ganglionic mass. The ganglion cells of the eighth cranial nerve (vestibularand cochlear) are derived from the otic placode and typically have 1–2 SC perganglion cell [28]. However, the ganglion cells of the seventh cranial nerve(geniculate and meatal) are derived from the epibranchial placode and the neuralcrest epithelium; these ganglia are normally surrounded by many SC, the precisenumber is not known.

Since the SC increase is part of the host response to NT virus infection ina ganglion, a significant increase in SC in the vestibular ganglion can be recog-nized with confidence, but not in the ganglia of the seventh nerve where a largenumber of SC is found normally. Therefore, evidence of ganglion cell degener-ation is necessary to conclude that NT virus has infected the geniculate and meatalganglia. Since direct evidence of ganglion cell degeneration is uncommonlyseen in the vestibular ganglion, it is necessary to rely on indirect evidence in theform of axonal degeneration to reflect NT damage of the vestibular ganglion.Since NT virus will typically also infect adjacent ganglion cells (clusters), focalaxonal degeneration in the vestibular nerve trunk represents virus destruction ofganglion cells. Focal axonal degeneration has been described in trigeminalnerve zoster [29].

Although viruses are protected within the environment of the ganglion celland nucleus, and therefore shielded from antibodies or antiviral drugs, their


infectious effects may be manifested by the release of nucleic acids [20]. Nucleicacids (DNA and RNA) have a low level of infectivity compared to the virus fromwhich they are derived. However, their release is capable of producing clinicalsyndromes similar to that resulting from virus infection and yet be unaffected bythe antibody response of the host since nucleic acids are not a viral protein.Nucleases released from blood components are capable of neutralizing nucleicacids. White blood cells may release nuclease inhibitors and consequently disturbthe normal equilibrium between nucleic acid infectivity and nuclease controlduring infection with fever (i.e. sinusitis). Fever as a precipitating effect in theclinical manifestation of a latent virus neuropathy may be understood in thecontext of this hypothesis.

Since exposure of the population to HSV is so high, reasons for the absenceof a similarly high incidence of cranial neuropathies should exist. Although thisevidence has not been reported, several possibilities exist.

(1) The makeup of the virus envelope as well as receptors on host neuronalmembrane represent a major determinant of virus invasion of a sensory ganglion.The glycoprotein composition of the virus envelope and compatible proteo-glycan receptors in the neuronal plasma membrane are genetically determinedfeatures of the virus-host neuron complex. The absence of surface structuresessential for virus attachment and invasion would present a major deterrent toNT invasion and establishment of latency in sensory nerves.

(2) The availability of sufficient ganglion cells to harbor a virus pathogenmay be important when the ganglion represents the initial repository for theinvading virus. The meatal ganglion of the facial nerve represents the locationfor neuronal pathology associated with vestibular ganglion degeneration in recur-rent vertigo possibly because it receives input from the soft palate and nasopharynxwhere virus invasion occurs [27, 30]. Since the meatal ganglion is represented bya very small ganglion cell population in most human temporal bones (TB), thelikelihood of a large virus load in this region of the facial nerve is correspond-ingly low.

(3) Host resistance reflects the genetic makeup of prospective neuronal elements (i.e. No. 1), as well as the genotype of the immune system (i.e. lym-phocytes) that are important for controlling virus invasion. The recrudescenceof virus from latency has frequently been noted with the immunocomprom-ised state (chemotherapy, radiation therapy) as well as with senescent immune systems.

NT viruses and their reactivation from latency assume a direction of flowwithin the central or peripheral processes of a sensory neuron dependent onvirus strain [31, 32]. The flow from neuron to the brainstem is referred to asanterograde flow, since it is in the direction of normal axoplasmic flow in theneuron, whereas flow toward the periphery (over the dendrite of the sensory

Gacek 8

neuron) is regarded as retrograde flow (fig. 1). The herpes family viruses are characterized by their ability to flow bidirectionally between the neuron and its peripheral or central terminus. Certain strains of the HSV preferen-tially travel in a retrograde direction (toward the periphery), and others flowpreferentially in an anterograde direction. The H 129 strain of HSV-1 flows inan anterograde direction while the McIntyre B strain follows a retrograde direc-tion of flow. This correlation is important, as to a large degree it may deter-mine the clinical presentation of reactivated virus. This principle provides thebasis for the use of NT viruses as a neurobiologic tracing method, since theanterograde virus strain will allow it to be transported centrally over severalsynaptic connections to demonstrate the higher neuronal members of a sensorysystem.

Intracellular pathogens have long been known to produce plaques as aresult of their cytopathic effect [33]. Uncommonly associated with bacterialpathogens such as Ehrlichia but commonly seen with viral agents such as vac-cinia, psittacosis, western equine encephalomyelitis virus and HSV, plaqueshave been used to detect and quantify virus presence in vitro because of the lin-ear relationship of plaque number with the number of virus particles. Plaquesize may differ with virus type and strain. Plaque shape is roughly sphericalwith a sharp border and represents necrosis of tissue.

Histological changes visible by light microscopy may reflect the accumu-lation of viral nucleic acids and antigen in cells infected with HSV. HeLa cellsinfected with HSV in tissue culture show that virus DNA accumulates intracel-lularly before viral antigen can be detected [34]. Successive stages show thatmore diffuse DNA accumulates as viral antigen is synthesized. These changesare also associated with the formation of giant cells which may represent fusionof infected individual cells. Since the nucleic acid content in cells is responsiblefor nuclear staining, it is possible that nuclear stains can demonstrate high intra-cellular levels of DNA accumulation. One component of the hematoxylin andeosin stain used in human TB histopathology is an excellent nuclear (nucleicacid) stain. Hematoxylin (C16H14O6) is the compound which results after etherextraction from the wood portion of Haematoxylon campechianum. Upon oxi-dation, hematoxylin is converted to hematein which stains certain structures(i.e. nuclei) a deep blue.

Histopathologic TB studies are important to our understanding of disorderscaused by viral organisms. Understanding the events which accompany NTviral infection and reactivation in sensory ganglia of the cranial nerves associ-ated with the TB can guide the interpretation of morphologic changes caused by these microorganisms. Complemented by direct immunofluorescence micro-scopy and molecular biology, an informative research approach can enhance thevalue of human TB collections.


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2 Straus SE: Clinical and biological differences between recurrent herpes simplex virus and varicella-zoster virus infections. JAMA 1989;262:3455–3458.

3 Baringer R, Swoveland M: Persistent herpes simplex virus infection in rabbit trigeminal ganglia.Lab Invest 1974;30:230–240.

4 Smith IW, Peutherer JF: The incidence of herpes virus hominis antibody in the population. J Hyg(Camb) 1967;65:395–408.

5 Whitley RJ: Herpes simplex viruses; in Fields BN, Knipe DM (eds): Virology, ed 2. New York,Raven Press, 1990, pp 1843–1888.

6 Laquerre S, Argnani R, Anderson D, Zucchini S, Manservigi R, Glorioso J: Heparan sulfate proteoglycan binding by herpes simplex virus type I glycoproteins B and C attachment, which differin their contributions to virus penetration, and cell-to-cell spread. J Virol 1998;72:6119–6130.

7 Forrester AJ, Farrell G, Wilkinson G, Kaye J, Davis-Poynter N, Minson AC: Construction andproperties of a mutant herpes simplex type I deleted for glycoprotein H sequences. J Virol1992;66:341–348.

8 Roop C, Hutchinson L, Johnson D: A mutant herpes simplex virus type I unable to express glyco-protein L cannot enter cells and its particles lack glycoprotein H. J Virol 1993;67:2285–2297.

9 Ligas MW, Johnson DC: A herpes simplex virus mutant in which glycoprotein D sequences arereplaced by B-galactosidase sequences binds to but is unable to penetrate into cells. J Virol1998;62:1486–1494.

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12 Nicola AV, Peng C, Lou H, Cohen GH, Eisenberg RJ: Antigenic structure of soluble herpes simplexvirus (HSV) glycoprotein D correlates with inhibition of HSV infection. J Virol 1997;71:2940–2946.

13 Herold RC, Wu Dunn D, Sultys N, Spear PG: Glycoprotein C of herpes simplex virus type I playsa principal role in the adsorption of virus to cells and infectivity. J Virol 1991;65:1090–1098.

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22 Dealty AH, Spivack JG, Lavi E, O’Boyle DR, Fraser NW: Latent herpes simplex virus type I transcripts in peripheral and central nervous system tissues of mice map to similar regions of theviral genome. J Virol 1988;62:749–756.

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Neuroanatomy of the Nerves in theTemporal Bone

Richard R. Gacek

The cranial nerves associated with the temporal bone (TB) have both sen-sory and motor components and may be invaded by neurotropic (NT) viruses.These are the fifth, seventh, eighth and ninth cranial nerves. NT (herpetic)involvement of the trigeminal nerve is a common viral neuropathy which hasbeen studied clinically by microbiologic and histopathologic methods [1, 2].However, virus-mediated neuropathy of the seventh, eighth and ninth cranialnerves has been a controversial subject. A viral etiology for idiopathic facialpalsy (Bell’s palsy) is now generally recognized [3–5]. Virus-mediated neuropa-thy of the eighth cranial nerve has only recently been supported by morphologicevidence in human TB [6]. Evidence to support a similar pathology in the ninthnerve is lacking thus far. Viral neuropathy of the tenth cranial nerve is also prob-able but is not included in this discussion since its anatomic course through theTB is not included in routine specimens. The eleventh cranial nerve is not affectedby NT viruses because it does not have a sensory component. The relationshipof these cranial nerves to areas of the oral cavity, oropharynx, nasopharynx andnose which are a habitat for NT viruses represents a basis for virus recrudescencefrom latency later in life.

Trigeminal Nerve

The trigeminal (fifth cranial) nerve is the largest of the cranial nerves andconveys common sensation from the superficial and deep regions of the face aswell as a smaller motor component to the muscles of mastication [7]. The fifthnerve trunk is attached to the lateral part of the pons by a large sensory root anda small motor root. The two nerve roots travel forward in the posterior cranial

Chapter 2

Neuroanatomy of the Nerves in the Temporal Bone 13

fossa to enter the middle cranial fossa after passing between the attachment ofthe tentorium cerebelli and the upper border of the petrous portion of the TB.The sensory root overlies the motor root as they pass into the trigeminal ganglionlying in Meckel’s cave on the superior surface of the petrous apex (fig. 1). Theganglion gives rise to the three main divisions of the nerve: ophthalmic, maxillaryand mandibular.

Details of the diverse functional components in these three divisions maybe found in texts of anatomy [7]. An overview of the sensory input conveyed by these divisions aids the understanding of the vulnerability of this cranialnerve to virus invasion. Although each division conveys common sensationfrom the upper, middle and lower thirds of the face as well as the anterior halfof the scalp, deeper structures lined with mucous membrane within bony cavi-ties of the skull are also richly innervated by the corresponding division.Accordingly, the ophthalmic division carries sensory input from the nasal cav-ity and ethmoid sinuses over the ethmoidal nerves, the maxillary division conveysinput from the alveolar ridge, maxillary and sphenoid sinuses (sphenopalatinenerves), and the mandibular division supplies the floor of the mouth and alveolus.NT viral invasion of the terminals (synaptosomes) and ganglion of the trigemi-nal nerve is made possible by nature of the epithelial surfaces in these areas.

Fig. 1. Low-power view of the trigeminal ganglion (T) in Meckel’s cave on the supe-rior surface of the petrous apex (PA). Figure 4 in the previous chapter 1 was taken from thissection.

Gacek 14

Facial Nerve

After emerging from the brainstem, the facial nerve (FN) travels togetherwith the vestibular division of the eighth cranial nerve the length of the internalauditory canal (fig. 2). The FN then enters the labyrinthine segment of the fal-lopian canal which conveys it throughout a tortuous course through the TB. TheFN is derived from the second branchial arch and innervates structures that arederived from Reichert’s cartilage. Four groups of functional neurons constitutethe FN complex [8].

(1) The special efferent FN axons supply the striated muscles of facialexpression, as well as the stapedius muscle, the stylohyoid muscle and the pos-terior belly of the digastric muscle.

(2) General visceral efferent fibers represent the preganglionic portion of theautonomic pathway to glandular and vascular structures (fig. 3). The main glan-dular structures are the lacrimal gland and the seromucinous glands in the nasal

Fig. 2. Photo of the FN (F) and vestibular nerve (V) in the internal auditory canal of adissected human TB. The myelinated nerves are stained with Sudan black. M � Location of themeatal ganglion adjacent to the vestibular ganglion; G � geniculate ganglion; S � saccule;U � utricular macula; LC, SC, PC � lateral, superior and posterior canal cristae.


cavity. These fibers travel in the greater superficial petrosal nerve (GSPN) tosynapse in the sphenopalatine ganglion, which contains the postganglionic neu-rons providing secretomotor function. Secretory fibers are carried by the chordatympani nerve and synapse with postganglionic neurons in the submandibularganglion innervating the submandibular and sublingual salivary glands.

(3) Special sensory fibers (taste) (fig. 4) are carried over two pathways. Themajority of the taste receptors inputting to the FN are located in the anterior twothirds of the tongue. Peripheral dendrites supplying these sensory receptors inthe chorda tympani nerve join their cell bodies in the geniculate ganglion (GG).A second group of taste receptors are located in the soft palate and nasopharyn-geal mucosa and are innervated by fibers in the GSPN which belong to ganglioncells (meatal ganglion, MG) located in the meatal segment of the FN.

(4) Somatic sensory neurons supply the skin of the external auditory canaland the concha.

The brainstem nuclei which give rise to FN axons are:(1) the motor nucleus of the FN, which is located in the caudal brainstem

adjacent to the superior olivary nucleus of the auditory system; just caudal to thefacial nucleus is the rostral limit of the nucleus ambiguus which provides motorinnervation to the intrinsic laryngeal musculature; the number of facial motorneurons has been estimated at approximately 10,000–20,000; the motor neuronsfor various facial muscle groups are topographically arranged in subnuclei

Superior SalivaryNucleus

VI

Motor NucleusN VII

Autonomic Pathways

Fig. 3. Diagram of the pre- and postganglionic parasympathetic motor pathways of the FN. VI � Abducens nucleus; N VII � seventh cranial nerve.

Gacek 16

within the facial nucleus [9]; however, the axons from these subnuclei intermixas they leave the facial nucleus in a dorsal direction to loop around the abducensnucleus near the floor of the fourth ventricle [10]; the axons converge at thispoint and then bend in a ventrolateral direction just medial to the vestibularnerve (VN) root before exiting the brainstem;

(2) the location of motor neurons for the stapedius muscle and the posteriorbelly of the digastric muscle are separately clustered in the brainstem; stapediusmotor neurons are located in the interface between the facial nucleus and thesuperior olivary nucleus, where they are strategically located to receive stimulifrom the afferent auditory pathway and carry out reflex contraction of thestapedius muscle (stapedius reflex); the motor neurons for the posterior belly ofthe digastric muscle are located along the course of the emerging FN root in thelateral brainstem region;

(3) the superior salivary nucleus is responsible for secretomotor (auto-nomic) neurons in the FN system; this nucleus is located dorsally to the motorfacial nucleus and gives rise to the preganglionic parasympathetic secretomotorneurons entering the submandibular and the sphenopalatine ganglia;

(4) the nucleus of the solitary tract, also located in the medulla, receivestaste input over sensory fibers of the FN.

The major portion of the FN is comprised of motor axons to the facial mus-culature. Although arising from regional groups of motor neurons in the facial

LacrimalGland

Trigeminal G.

GSPN Meatal G.

VIMotor NucleusN VII

Nucleus &TractSolitarius

MotorFacialNerve

Sublingual &SubmandibularGlands

Submandibular G.

Special Sensory Pathways

Geniculate G.

Lingual Nerve

Nasal &PalatineGlands

PterygopalatineGanglionPalate

Fig. 4. Diagram of the special sensory pathways of the FN. G � Ganglion;VI � abducens nucleus; N VII � seventh cranial nerve.


nucleus, these fibers intermix throughout the course of the FN in its intracranialand intratemporal segments [10]. After exiting the stylomastoid foramen, themotor axons gather together in functional groups before forming the 4–5branches which supply the regional facial muscle groups. For purposes of thisdiscussion, the important divisions of the FN trunk are the meatal segment, thelabyrinthine (petrosal) portion, the geniculate portion and the tympanic part(fig. 5). Except for the meatal portion which lies free in the internal auditorycanal, the remaining segments of the FN are contained within a bony canal (fal-lopian). Accompanying the FN trunk is the nervus intermedius which carriessecretomotor axons of the preganglionic neurons in the superior salivary nucleus,as well as proximal axons of sensory neurons in the FN ganglia (geniculate andmeatal), traveling to the nucleus solitarius in the brainstem.

Fig. 5. Low-power view of the tympanic (T), geniculate (G), petrosal (P) and meatal (M) segments of the FN. V � Vestibular ganglion; C � basal turn of the cochlea.

The sensory ganglia of the FN (geniculate and meatal) are important to thesubject of virus-mediated neuropathy (fig. 6). A quantitative study of 100 TBdescribed these ganglionic masses quantitatively (fig. 7) [11]. These two gangliaare derived from different embryologic anlagen, the GG from the epibranchialplacode (second branchial arch), while the MG develops from the neural crestprimordium. In most TB (88%), the GG contains most of the sensory neurons inthe FN while the MG is very small. In approximately 12% of FN, the MG may

Fig. 6. a Photograph of the GG (G) at the junction of the tympanic (T) and petrosal (P)segments of the FN. b The MG of the FN (F) is located adjacent to the vestibular ganglion (V).

Com

posi

tion

(%)

100

80

60

40

20

00 20 40 60 80 100

Cases (n)

Fig. 7. Graphic ordering of the percentage composition of the FN ganglia (geniculateand meatal) in 100 human TB. � � Meatal; � � geniculate.

Gacek 18


equal or exceed the number of ganglion cells in the GG. The study found thatthe number of neurons in the GG ranged from 66 to 4,017 (mean 1,713) whilethe MG contained from 0 to 2,764 cells (mean 448). Fourteen percent of the GGcontained less than 1,000 cells, while 88% of the MG contained under 1,000cells. Sixty-four percent of the MG held fewer than 500 cells, and 34% had lessthan 200. In approximately 2% of TB, the MG represents the entire ganglionassociated with the FN.

In instances where the GG is absent and the MG represents the only sen-sory ganglion of the FN, TB specimens indicate that the GSPN inputs to the MG(fig. 8). This observation supports a conclusion that the afferent input from tastereceptors in the soft palate and nasopharynx is carried over the GSPN to theMG, while the GG contains sensory neurons for taste receptors in the anteriortwo thirds of the tongue [11]. Furthermore, the MG location in the inner audi-tory canal portion of the FN is juxtaposed to the vestibular ganglion (Scarpa’sganglion; fig. 6b). Although these two ganglionic masses are derived from twoseparate embryologic sources, their intimate anatomic association permits acommon involvement in inflammatory processes [6].

Eighth Cranial Nerve

The eighth cranial nerve is made up of two portions, the vestibular and thecochlear, supplying the balance and the auditory portions of the labyrinth,respectively. Both of these nerve divisions are primarily afferent in function and

Fig. 8. a In this case where the GG is absent (*), the greater superficial petrosal nerve(GSP) travels toward the labyrinthine segment (L) of the FN. T � Tympanic FN. b A large MGrepresents the sensory ganglion of the FN (F) when the GG is missing. V � Vestibular ganglion.

Gacek 20

composed of bipolar ganglion cells derived from the auditory vesicle [8]. Theyare of placodal origin. The human VN is comprised of approximately 18,000bipolar neurons, of which a third are classified as large afferents and two thirdsare small afferents. The large and small afferent neurons supply hair cells in allfive vestibular sense organs. The large afferents supply the type 1 hair cells witha calyx-like ending, in a 1 : 1 or 1 : 2 ratio (fig. 9). The small afferents supplytype 2 hair cells in the vestibular sense organs with small bouton-type endings.Each small afferent fiber branches generously to contact type 2 hair cells over awide area in the sensory epithelium. There is an orderly distribution of type 1and type 2 hair cells in the sense organs [12]. In the crista of the three semicircularcanals, type 1 hair cells are located primarily at the crest of the crista, whereastype 2 hair cells predominate along the slopes. In the maculae of the utricle andthe saccule, type 1 hair cells predominate near the striola line of the macula,whereas the type 2 hair cells are denser over the peripheral regions. The two

Kinocilium

Stereocilia

Efferentnerve ending

Afferentnerve ending

Type 2

Hair cells

Type 1

Cuticle

KC

Supporting cell

Nerve chalice

Synaptic bar

Efferentnerve ending

Fig. 9. Drawing of the afferent and efferent innervation of type 1 and 2 vestibular haircells. KC � Kinocilium.


types of afferent neurons in the VN possess different neurophysiologic proper-ties. The large afferents supplying type 1 hair cells display an irregular sponta-neous discharge pattern, while the small afferents to type 2 hair cells exhibit aregular spontaneous discharge pattern [13, 14]. Each ganglion cell in the humanVN is normally surrounded by 1–2 satellite cells which have an important andclose metabolic relationship to its ganglion cell [15]. The distribution and courseof the bipolar afferent neurons in the VN are organized as to their projection pat-tern from sense organs (fig. 10) [16]. The lateral and superior canal cristae ofthe superior vestibular division input to the brainstem over large afferent gan-glion cells in the most anterior portion of the vestibular trunk, which are closestto the MG in the FN. The small afferents supplying type 2 hair cells in the lateraland superior canal cristae are located in a more caudal portion of the superiordivision of the VN, while the ganglion cells supplying the utricular macula lie in

SCA

HCA

Utricle

Saccule

PCA

SG

Saccular nerve

OCB

Utricular nerve

PCN

Fig. 10. Drawing of the input from vestibular sense organs in the ear. The dark area fromthe superior (SCA) and lateral (HCA) canals is closest to the FN. PCA � Posterior canalcrista; SG � Scarpa’s ganglion; OCB � olivocochlear bundle; PCN � posterior canal nerve.

Gacek 22

the inferior portion of the superior vestibular division. The ganglion cells for the posterior canal crista are located most caudally in the inferior vestibularganglion and project their axons rostrally to join those of the superior divisioncristae before entering the brainstem. The saccular ganglionic input is located in the most caudal portion of the VN trunk. The distal process (dendrite) ofvestibular ganglion cells is approximately half the diameter of the proximalaxon and is intermixed in the nerve branches before terminating in the senseorgan neuroepithelium. On the other hand, the proximal axons of ganglion cellsproject in a straightforward fashion from Scarpa’s ganglion cells to the brain-stem. Therefore, degeneration of the thicker proximal axons in the nerve trunkis more easily detected by light microscopy than degeneration of the thinner distal process (dendrite) in VN branches.

The efferent pathway to the vestibular labyrinth arises from small neuronslocated bilaterally near the medial vestibular nucleus and the abducens nucleusclose to the floor of the fourth ventricle (fig. 11) [17]. The number of efferentneurons supplying the cat labyrinth is approximately 200–300 [18]. However,because of a profuse branching pattern, the number of efferent terminals almost

Cerebellum

Coch. eff.

ASOASO

MVNLVN

VVCN

DCN

LSO

V

LVN

VCN

MVN

VIIVI

VII

VII

Fig. 11. Drawing of the origin and course of the efferent vestibular pathway. The stippledarea denotes the efferent cochlear pathway. DCN � Dorsal cochlear nucleus; VCN � Ventralcochlear nucleus; LVN � Lateral vestibular nucleus; MVN � Medial vestibular nucleus;V � Descending trigeminal nucleus; VII � Facial nerve genu; ASO � Accessory superior olivary nucleus; VI � Abdueens nucleus; LSO � Lateral superior olivary nucleus; Coch.eff. � Cochlear efferent.


Fig. 12. Cross-section of the seventh and eighth nerves of the cat stained for acetyl-cholinesterase. EF � Efferent fibers (cochlear and vestibular) bundle in the VN (V);C � cochlear nerve; F � FN; NI � nervus intermedius.

equals the number of afferent terminals provided by 12,000 afferent neurons [19].Fine efferent axons collect as they travel laterally before entering the vestibularroot in the brainstem, join the efferent cochlear fibers (olivocochlear bundle)and travel together as a compact group of small axons in the VN (fig. 12). Thesefine axons emerge from the brainstem between the superior and inferior VN divi-sions [19]. At the saccular portion of Scarpa’s ganglion, the efferent axons passthrough the ganglionic mass and then diverge toward the sense organs (fig. 13).Vestibular efferents are dorsally located in the parent efferent bundle before dispersing into the superior and inferior vestibular divisions, first in fasciclesand then as individual fibers which branch as they travel peripherally (fig. 14).After penetrating the basement membrane of the sense organs, they ramify fur-ther before forming many vesiculated small bouton terminals contacting type 2hair cells predominantly [20, 21]. Efferent termination also occurs on the largecalyx-like endings which engulf type 1 hair cells. The density of efferent termi-nals is greatest on the type 2 hair cells along the slopes of the cristae and inperipheral regions of the maculae [21]. Efferent fibers are cholinergic and thedistribution of efferent fibers can be selectively demonstrated by using a histo-chemical method to localize acetylcholinesterase activity [19].

Gacek 24

The human cochlear nerve is composed of approximately 30,000 bipolarganglion cells, of which 95% are type 1 with myelinated axons, and 5% are type 2ganglion cells with unmyelinated cell processes [22]. The type 1 spiral ganglioncells project in a straightforward manner to the inner hair cells (IHC) of theorgan of Corti where they terminate directly on the IHC (fig. 10). Since approx-imately 10–20 type 1 dendrites terminate on each IHC, the innervation patternis very dense at the base of the IHC (fig. 15). The spontaneous discharge patternof these type 1 ganglion cells is irregular, somewhat similar to the large affer-ents in the vestibular ganglion which terminate on type 1 vestibular hair cells.The small type 2 spiral ganglion cells project fine unmyelinated dendrites alongthe floor of the tunnel space in the organ of Corti, enveloped by tunnel cellprocesses to form spiral fiber bundles between Deiters’ cells and terminate onouter hair cells (OHC) in a diffuse pattern (fig. 16). They travel basally in a lon-gitudinal direction before terminating on OHC [22]. The central termination oftype 2 ganglion cells is unknown, although it has been suggested that they ter-minate in the dorsal cochlear nucleus. The function of type 2 spiral ganglioncells is unknown at this time.

Fig. 13. A more distal section of the same specimen as in figure 12 demonstrates theolivocochlear bundle (OCB) as it leaves the saccular nerve (S) to join the cochlear nerve (C).Vestibular efferent fibers (VE) travel as bundles in the superior division and as scatteredfibers in the posterior canal nerve (PC) and saccular nerve. F � FN.


The efferent cochlear system (olivocochlear bundle) has been described forover 50 years as having a bilateral origin with the major portion of the efferentaxons to one cochlea arising from periolivary neurons near the contralateralaccessory superior olivary nucleus in the brainstem (fig. 17) [24–26]. Thesemyelinated axons pass in a dorsal direction before decussating under the floor ofthe fourth ventricle with the contralateral olivocochlear bundle and interdigitatewith FN fibers before merging with the vestibular efferent bundle in the VNroot. They are then joined by the ipsilateral limb of the olivocochlear bundlewhich is given off by small neurons surrounding the lateral superior olivarynucleus. The efferent neuronal supply to the cat cochlea numbers 1,500–2,000compared to 50,000 afferent ganglion cells in the cat [26]. As with vestibularinnervation, extensive branching in the efferent system accounts for near equal-ity in the number of afferent and efferent terminals within the organ of Corti.Numerically, the ipsilateral limb of the olivocochlear bundle is about 25% of thesize of the contralateral limb. Furthermore, the axons in the ipsilateral olivo-cochlear bundle are unmyelinated or thinly myelinated while those in the con-tralateral limb are well myelinated. These cochlear efferent axons, together withvestibular efferent fibers, travel in the VN through the saccular portion of the

Fig. 14. A high-power view of the posterior canal nerve shows the individual efferentnerve fibers (arrows) scattered throughout the nerve. Ganglion cells are in the upper left corner.

Gacek 26

Fig. 15. A transmission electron micrograph of the base of IHC shows bundles of nerve fibers (NF) and endings (NE) tightly surrounded by supporting cells (S) after penetrating the basilar membrane (BM). Efferent fibers in a spiral bundle (E) pass near thehair cell.

Fig. 16. A phase contrast micrograph of the organ of Corti in the cat illustrates the relationship of outer spiral bundles (open arrows) at the base of OHC. D � Deiters’ cells;H � Hensen’s cells; P � pillars; S � supporting cells with IHC; T � tectorial membrane.


vestibular ganglion before the efferent cochlear fibers emerge as the vestibulo-cochlear anastomosis (Oort’s), enter Rosenthal’s canal and then travel apicallyin a spiral direction as the intraganglionic spiral bundle. As the bundle travelsapically in the cochlea, it gives off individual fibers which mix with afferentdendrites within the osseous spiral lamina before exiting through the habenulaperforata to enter the organ of Corti.

Since cochlear efferent axons are also cholinergic, the acetylcholinesterasetechnique has been used to demonstrate their course and termination. The fibersof the contralateral olivocochlear bundle cross high in the tunnel space and giverise to large vesiculated terminals which contact the base of OHC (fig. 18, 19).The density of the efferent innervation of OHC is greatest in the upper basalturn, with decreasing innervation density in both apical and basal directions[27]. This decrease is seen first in the outermost row of OHC, then the middleand innermost OHC in the apical direction. The smaller fibers of the ipsilateralefferent system form a dense inner spiral bundle of fibers under the IHC whichprovides contact by small bouton-shaped endings on afferent axons near theirtermination on IHC.

Glossopharyngeal Nerve (Ninth Cranial Nerve)

Although the ninth cranial nerve has a motor component to the stylopha-ryngeus muscle, it is largely a sensory nerve which innervates the carotid body,

Fig. 17. Drawing of the origin and course of the olivocochlear efferent bundle byRasmussen [24].

Gacek 28

Fig. 19. An electron micrograph at the base of an OHC in the guinea pig demonstrateslarge efferent terminals (E) filled with vesicles and an afferent ending (A) from type 2 spiralganglion cells.

Fig. 18. An acetylcholinesterase preparation of the guinea pig organ of Corti demon-strates the course and termination of efferent fibers (EF). Large terminal swellings are locatedat the base of OHC, while the large accumulation under an IHC represents inner spiral fibersas well as terminals on afferent endings.


the pharyngeal tonsil, the base of the tongue and the lingual surface of theepiglottis. Sensory taste receptors located in the posterior third of the tongue,the adjacent epiglottis and the soft palate project over the glossopharyngealnerve and ganglion to the nucleus solitarius in the brainstem (fig. 20). Ganglioncells responsible for these sensory inputs are located in the inferior ganglionwithin the jugular foramen. A smaller superior ganglion is variably present andmay contain sensory neurons of the tympanic branch.

The tympanic branch of the ninth nerve is important clinically because itcarries preganglionic efferent parasympathetic axons as well as afferents frommiddle ear mucosa through the middle ear space as Jacobson’s nerve which con-tinues as the lesser superficial petrosal nerve before synapsing in the otic gan-glion. Postganglionic neurons in the otic ganglion complete the efferent link tothe parotid salivary gland.

The presence of sensory ganglion cells carrying input from taste receptorsin the oral cavity over the seventh and ninth cranial nerves represents a commonpathway for entrance of NT viruses into these cranial nerves. NT viral gan-glionitis as a cause of recurrent ear pain requires morphologic evidence inhuman TB.

Middle ear

Otic ganglionJugularforamen

Superiorganglion

Inferiorganglion

Brainstem

Inferior salivatorynucleus

Motor nucleus

NucleussolitariusTympanic

nerve

Internal carotid artery

Carotid bodyStylopharyngeusmuscle

Externalcarotid artery

Soft palate

Tonsil

Tongue

Parotid

Fig. 20. Drawing summarizing the afferent and efferent projections of the glosso-pharyngeal (ninth) nerve. Note that the tympanic nerve contains both afferent and efferentnerve fibers.

References

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2 Baringer RJ, Swoveland MA: Persistent herpes simplex virus infection in rabbit trigeminal ganglia.Lab Invest 1974;80:230–240.

3 Adour K, Bell DN, Hilsinger R: Herpes simplex virus in idiopathic facial paralysis (Bell’s palsy).JAMA 1975;233:527–530.

4 Burgess RC, Michaels L, Bole JF, Smith RH: Polymerase chain reaction amplification of herpessimplex viral DNA from the geniculate ganglion of a patient with Bell’s palsy. Ann Otol RhinolLaryngol 1994;103:775–779.

5 Gacek R, Gacek M: Meatal ganglionitis: Clinical pathologic correlation in idiopathic facial paral-ysis (Bell’s palsy). Otorhinolaryngol Nova 1999;9:229–238.

6 Gacek R: The pathology of facial and vestibular neuronitis. Am J Otolaryngol 1999;20:202–210.7 Dunward A: Peripheral nervous system – Trigeminal nerve; in Brash JC (ed): Cunningham’s Text

Book of Anatomy. Oxford, Oxford University Press, 1951, pp 1018–1028.8 Gacek R, Gacek M: Anatomy of the auditory and vestibular systems; in Ballenger J, Snow J (eds):

Ballenger’s Otorhinolaryngology, Head and Neck Surgery, ed 16. San Diego, Singular Publications,San Diego, in press.

9 Radpour S, Gacek RR: Further observations on the organization of the facial nucleus. Laryngoscope1980;90:685–692.

10 Gacek RR, Radpour S: Fiber orientation of the facial nerve: An experimental study in the cat.Laryngoscope 1982;92:547–556.

11 Gacek RR: On the duality of the facial nerve ganglion. Laryngoscope 1998;108:1077–1086.12 Wersall J, Flock A, Lundquist RG: Structural basis for directional sensitivity in cochlear and

vestibular sensory receptors. Cold Spring Harbor Symp Quant Biol 1965;30:115–132.13 Walsh BT, Miller JB, Gacek RR, Kiang NYS: Spontaneous activity in the eighth cranial nerve of

the cat. Int J Neurosci 1972;3:221–236.14 Goldberg JM, Fernandez C: Physiology of peripheral neurons innervating semi-circular canals

of the squirrel monkey. I. Resting discharge and response to constant angular accelerations. J Neurophysiol 1971;34:635–660.

15 Ona A: The mammalian vestibular ganglion cells and the myelin sheath surrounding them. ActaOtolaryngol (Stockh) 1993;suppl 503:143–149.

16 Gacek RR: The course and central termination of first order neurons supplying vestibular endorgans in the cat. Acta Otolaryngol (Stockh) 1969;suppl 254:1–66.

17 Gacek RR, Lyon M: The localization of vestibular efferent neurons in the kitten with horseradishperoxidase. Acta Otolaryngol (Stockh) 1974;suppl 77:92–101.

18 Gacek RR: Efferent component of the vestibular nerve; in Rasmussen GL, Windle WF (eds): Neural Mechanisms of the Auditory and Vestibular Systems. Springfield, Thomas, 1960, pp 276–284.

19 Gacek RR, Nomura Y, Balogh K: Acetyl cholinesterase activity in the efferent fibers of the stato-acoustic nerve. Acta Otolaryngol 1965;59:541–533.

20 Wersall J: Studies on the structure and innervation of the sensory epithelium of the cristaeampullares in the guinea pig: A light and electron microscope investigation. Acta Otolaryngol(Stockh) 1956;suppl 126:1–85.

21 Smith CA, Rasmussen GL: Nerve endings in the maculae and cristae of the chinchilla vestibule,with a special reference to the efferents. 3rd Symp Role Vestib Organs Space Exploration, NASAStatus Post-152, Washington, USGPO, pp 183–201.

22 Spoendlin H, Schrott A: The spiral ganglion and the innervation of the human organ of Corti. ActaOtolaryngol (Stockh) 1990;105:403–410.

23 Spoendlin HH, Gacek RR: Electron microscopic study of the efferent and afferent innervation ofthe organ of Corti in the cat. Ann Otol Rhinol Laryngol 1963;72:660–687.

24 Rasmussen GL: The olivary peduncle and other fiber projections of the superior olivary complex.J Comp Neurol 1946;84:141–220.

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25 Rasmussen GL: Further observations of the efferent cochlear bundle. J Comp Neurol 1953;99:61–74.

26 Warr B, Guinan J, White JS: Organization of the efferent fibers: The lateral and medial olivo-cochlear systems; in Altschuler RA, Hoffman GW, Bobbin RP (eds): Neurobiology of Hearing:The Cochlea. New York, Raven Press, 1986, pp 333–348.

27 Ishii D, Balogh K: Distribution of efferent nerve endings in the organ of Corti: Their graphicreconstruction in cochleae by localization of acetylcholinesterase activity. Acta Otolaryngol(Stockh) 1968;66:282–288.



Meatal Ganglionitis: A PathologicCorrelate in Idiopathic Facial Paralysis

Richard R. Gacek, Mark R. Gacek

Evidence from many sources has accumulated to support the concept thatidiopathic facial paralysis (IFP) is an inflammatory neuropathy caused by a neuro-tropic (NT) virus of the herpes simplex or zoster family [1–10]. Because of thehigh exposure to these viruses in the general population, numerous nerves in thebody are exposed to NT viruses which then have the tendency to acquire a latentform within sensory ganglion cells of peripheral nerves. The previous chaptershave described the biology of herpes simplex ganglionitis and the propensity ofthe virus to remain in a latent form within the ganglion from which it can bereactivated at a later time [11]. Although the sensory ganglion cell is the locusof inflammation, the motor portion of the facial nerve (FN) may be affectedbecause of a demyelinating autoimmune response to the viral agent in the gan-glion cells [12, 13]. It is also probable that various virus types and strains, aswell as host resistance, play a role in the clinical manifestation of IFP.

Although it has generally been assumed that the geniculate ganglion (GG)is the site of virus accumulation in IFP [14], ganglion cell degeneration withinthe GG has never been described. On the other hand, recent attention has beencalled to the meatal ganglion (MG) which is located in the meatal segment ofthe FN [15, 16]. While the MG is present in all human temporal bones (TB), ithas a relatively minor presence compared to the GG in most TB. However, in12% of TB, the MG may be as large or even exceed the GG in ganglion cellnumber. Clinical observations made by Fisch and Esslen [17] indicated that themost prominent location of FN swelling and edema is in the meatal segment(that portion of the nerve that is proximal to the meatal foramen). The postulateddural constriction at the entrance to the labyrinthine fallopian canal was felt tobe responsible for obstruction of axoplasmic flow which then causes a physio-logic decrease in nerve conduction. Surgical decompression of this portion ofthe FN canal was felt to be important in the treatment of IFP.

Chapter 3

In 1999, we reported TB findings in a patient with IFP 6 years before death,with subsequent complete recovery of the facial paralysis [18]. This patient hadundergone radiation therapy to the spleen for chronic lymphocytic leukemia. Nodegenerated ganglion cells were found in the GG of the TB, but there were sev-eral degenerated ganglion cells in the MG. The adjacent vestibular ganglion tothe MG carrying innervation to the lateral and superior canal cristae was com-pletely degenerated, and focal axonal degeneration was also seen in the vestibu-lar nerve trunk. The concept is formed that IFP results from meatal ganglionitisrather than geniculate ganglionitis. It is possible that the GG is involved in theprogression of IFP, since the two ganglia are connected by the nervus inter-medius. The present report describes 6 TB from 4 patients with IFP. The majorfinding was a confirmation of degenerated ganglion cells in the MG of the FNand not the GG.

Materials and Methods

(1) A case report describes the MRI findings in a patient with IFP that was monitoredat 1, 8 and 15 weeks after the onset of paralysis. Spontaneous and complete recovery of facialfunction occurred within 2 months in this patient. Six additional patients with IFP were fol-lowed with MRI.

(2) Eleven published studies [19–29] describing the use of MRI in IFP were reviewedcomparing the location of enhancement in the FN during the disorder. These studies includedpatients who were monitored within 7 days as well as several weeks to months following theonset of paralysis.

(3) Six horizontally sectioned TB from 4 patients with a history of IFP were examinedfor morphologic changes in the FN as well as vestibular and cochlear ganglia which correlatewith the FN paralysis. These TB were formalin fixed, decalcified, embedded in celloidin andsectioned at 20 �m thickness. Every tenth section was stained with hematoxylin and eosin,cover-slipped and examined in a light microscope.

Results

Case Report

A 51-year-old female with a 7-day history of complete left facial paralysis(grade VI/VI House-Brackman), otalgia and vertigo had an otherwise normalhead and neck examination. The remaining cranial nerve function includinghearing was normal. The patient had been treated with oral prednisone (40 mgdaily) since the onset of facial weakness. Famvir (500 mg t.i.d.) was added to thesteroid management. An enhanced MRI at this time revealed localized enhance-ment in the meatal segment of the left FN (fig. 1).

Meatal Ganglionitis: A Pathologic Correlate in Idiopathic Facial Paralysis 33

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Medical treatment was discontinued after 1 additional week because thepatient demonstrated spontaneous partial recovery of function (grade III/VI).Six weeks later, when the left facial weakness had improved significantly (gradeI/VI), an MRI with gadolinium showed enhancement of the geniculate, tympanicand mastoid FN segments in addition to the meatal FN enhancement (fig. 2).MRI 15 weeks after onset of IFP demonstrated enhancement of the GG andgreater superficial petrosal nerve but none in the meatal segment (fig. 3).

We have performed MRI on 6 additional patients with IFP. All demon-strated enhancement in the meatal segment of the FN during the first 2 weeksafter onset of paralysis.

MRI Studies

Table 1 lists 11 MRI studies of the FN in IFP reported from the years 1989–1997 [19–29]. These studies are representative of the FN imaging studies dealingwith IFP likely caused by herpes simplex virus type 1 (HSV-1) and varicella-zoster

Fig. 1. Coronal (a) and axial (b) Gd-DTPA MRI demonstrates localized enhancementin the internal auditory canal of a left TB (arrow) 7 days after onset of left IFP.


Fig. 2. Coronal (a) and axial (b) enhanced MRI 6 weeks after IFP onset demon-strates enhancement in the geniculate (G), proximal tympanic and mastoid (MA) segments ofthe FN.

Fig. 3. Axial enhanced MRI at 15 weeks after onset of IFP demonstrates enhancementin the GG (G) and greater superficial petrosal nerve (GSP) but minimal change in thelabyrinthine segment (L) of the FN.

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virus. Careful evaluation of enhancement in the FN in an inflammatory disordersuch as IFP requires consideration of enhancement in the geniculate, tympanicand mastoid FN segments caused by pooling of gadolinium in the vascular net-work of the sheath surrounding the nerve in these portions of the fallopiancanal. Enhancement of the FN in these regions is frequently seen with increasedtime after onset of IFP. This is due to increased intraneural edema and inflam-matory dilatation of the perineural vessels in these segments [30]. Therefore,enhancement in the FN most reliably reflects an inflammation in the meatal andlabyrinthine segments. In 7 of the studies [19, 20, 22, 24, 27–29], enhancementoccurred in the meatal FN segment in the majority of the patients with IFP. All11 series reported enhancement in the meatal FN. Seven studies recordedpatients where no enhancement was found in the ipsilateral FN. Of the remain-ing 4 reports, 2 series [21, 28] recorded no FN without enhancement while 2other reports [23, 26] gave no information.

TB Reports

Table 2 summarizes morphologic changes in the seventh and eighth cranialnerves in the TB of the 4 patients with IFP. The ages of the 4 patients with IFPranged from 56 to 74 years; there were 2 males and 2 females. One patient

Table 1. MRI of FN in IFP

Authors Year Patients Enhancement No enhancement

ME L G T MA

Daniels et al. [19] 1989 4 3 3 3 3 3 1Schwaber et al. [20] 1990 17 15 13 13 12 13 1Tien et al. [21] 1990 8 2 8 8 8 8 0Doringer et al. [24] 1991 11 9 10 – 7 8 1Matsumoto et al. [23] 1991 46 11 13 37 32 28 –Murphy and Teller [25] 1991 25 3 11 16 11 2 7Yanagida et al. [26] 1991 63 15 20 25 25 49 –Korzec et al. [22] 1991 10 7 7 4 4 3 3Engstrom et al. [27] 1993 21 10 – 2 0 2 9Kohsyu et al. [28] 1994 22 18 22 22 22 22 0Engstrom et al. [29] 1997 11 8 3 4 1 3 3

– � Not given; ME � meatal; L � labyrinthine; G � geniculate; T � tympanic; MA � mastoid.


(A.B.) had a history of a partial facial paralysis with complete recovery 6 yearsbefore her death from chronic lymphocytic leukemia. This TB has previouslybeen reported [18]. The remaining 3 patients had facial paralysis (partial 1, total 2)at the time of death. Patient E.J. had right total facial paralysis from herpeszoster oticus. Degeneration of ganglion cells or the FN in its meatal segmentwas seen in all but 1 TB. No degenerated cells were observed in the GG of anyof the 6 TB. The vestibular ganglion was partially or totally degenerated in 4 TB,and cochlear neurons were significantly degenerated in all 6 TB. In 1 case withbilateral facial paralysis, there was significant swelling of the FN proximal tothe meatal foramen on both sides.

Case 1At the age of 78 years, this patient experienced sudden onset of partial right

FN paralysis which recovered completely in 10 days. She did not complain ofhearing loss or vertigo. Three years before she had been diagnosed as havingchronic lymphocytic leukemia which was treated by radiation therapy to thespleen. During the remaining 6 years of life she had recurrent episodes of

Table 2. Pathology in IFP (n � 6 TB)

Patient Age Sex Otologic Cause of death FP FS Degeneration(years) diagnosis

GG MG vestibular spiralganglion ganglion

A.B. 81 F SOM chronic lymphocytic R 0 0 � � (SC moderate leukemia and LC) deg.

R.D. 56 F deg. coch. oat cell carcinoma of P 0 0 � total loss total lossand vest. the lung/terminal nerves pneumonia

W.R. (L) 74 M SNHL myocardial infarction T � 0 � � (LC) 50% loss(severe)

W.R. (R) 74 M SNHL myocardial infarction T � 0 0 0 60% loss(severe)

E.J. (R) 72 M herpes zoster leukemia T 0 0 meatal � severe 90% lossoticus, FN comp. deg.otosclerosis deg.

E.J. (L) 72 M otosclerosis leukemia 0 0 0 � 0 90% loss

FP � Facial paralysis; R � resolved; P � partial; T � total; FS � facial nerve swelling; SOM � serous otitis media;deg. � degeneration; coch. � cochlear; vest. � vestibular; comp. � complete; SNHL � sensorineural hearing loss;SC � superior semicircular canal; LC � lateral semicircular canal.

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septicemia treated with antibiotics. Her death was caused by overwhelming septicemia.

Histopathology of the Right TB: Postmortem Time 13 h. The middle earmucosa was hypertrophic and contained numerous foci and diffuse infiltrationof lymphocytes. There were numerous fascicles of regenerating myelinatednerve fibers passing around the GG. Numerous mononuclear cells resemblingsatellite cells filled the space between GG neurons. No degenerated ganglioncells were seen in the GG (fig. 4).

Ganglion cells in the MG and scattered between sensory fibers of the FNwere surrounded by an increased number of satellite cells. There were severaldegenerated ganglion cells in the MG (fig. 5), and degenerated axons werefound in the nervus intermedius of the FN.

There was a loss of dendrites to the cristae ampullares of all three semi-circular canals (fig. 6) while the utricular (fig. 7) and saccular nerve brancheswere normal. Scarpa’s ganglion contained approximately 30% loss of ganglioncells and the remaining cells were surrounded by an increase in satellite cells.Focal axonal degeneration was present in the vestibular nerve trunk (fig. 8). Therewas a patchy loss of the organ of Corti throughout the basal turn of the cochlea.Atrophy of the stria vascularis was present in the middle and upper basal turns.

Fig. 4. The GG in an 81-year-old female (case 1) with recovered IFP contained manysatellite cells (arrows) but no degenerated ganglion cells.


Fig. 5. The MG (case 1) was composed of degenerated (arrow) as well as intact ganglion cells (M). F � FN.

Fig. 6. There was complete degeneration of vestibular nerve fibers to the superior andlateral (LC) canal sense organs (arrow).

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Fig. 7. The innervation of the utricular macula (U) was intact (arrow).

Fig. 8. Focal axonal degeneration (arrow) was seen in the vestibular nerve trunk.VG � Vestibular ganglion.


Case 2This female experienced dysphagia from the age of 53 years to 55 years

when she underwent surgery to relieve a stenosed cardiac sphincter. At the age of56 years, she experienced hearing loss in her left ear and vertigo. A hearing testrevealed a profound hearing loss in the left ear (discrimination � 0%) and amixed hearing loss in the right ear (speech reception threshold � 22 dB; discrim-ination � 96%). There was a spontaneous nystagmus to the right and no caloricresponse in the left ear but a normal response in the right ear. She subsequentlydeveloped weakness of the upper arms, hands and neck, and a partial weakness ofthe muscles of the left side of the face. Postmortem examination revealed oat cellcarcinoma of the right upper lobe with hilar lymph node metastases.

Histopathology of the Left TB: Postmortem Time 13 h. The organ of Cortiwas normal except for the basal 9 mm where there was a total loss of hair cells.There was a total loss of vestibular neurons (fig. 9, 10). Efferent axons remainedin Rosenthal’s canal as well as in the peripheral vestibular nerve branches. Thevestibular sense organs were normal. Several degenerated and intact ganglioncells in the MG of the FN were surrounded by a plethora of satellite and inflam-matory cells (fig. 11). Although there were many satellite cells in the GG, nodegenerated ganglion cells were found (fig. 12).

Case 3This 74 year old male had mild difficulty walking at the age of 61 years. He

had progressive difficulty walking and occasionally fell. At the age of 70 years,

Fig. 9. Case 2. Complete degeneration of innervation (arrow) to the lateral canal (LC)and superior canal cristae.

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he noted clumsiness of his hands. At the age of 71 years, he exhibited a cog-wheel rigidity of his upper extremities and facial weakness bilaterally. He wasdiagnosed as having Charcot-Marie-Tooth syndrome and Parkinson’s disease.Since facial weakness is not part of Charcot-Marie-Tooth syndrome, it was feltthat his facial weakness was idiopathic or part of Parkinson’s disease.

Histopathology of both TB: Postmortem time 3 h. There was total loss ofthe organ of Corti in the right ear and a scattered partial loss in the left ear.Severe atrophy of the stria vascularis and spiral ligament was present in the sec-ond and third turns of both ears. There was 50% loss of cochlear neurons in allturns of both cochleae. The vestibular labyrinths were severely distorted by arti-fact incurred during removal of the TB. The facial nerves in both TB showedmarked enlargement proximal to the meatal foramen (fig. 13). There were nodegenerated neurons in the GG, but many satellite cells surrounded neural ele-ments (fig. 14). There were 1–2 degenerated ganglion cells in the MG of the leftFN (fig. 15) adjacent to a fascicle of degenerated axons in the vestibular nervetrunk (fig. 16).

Case 4At the age of 70 years, a hearing test revealed bilateral sensorineural hear-

ing loss with a descending audiometric pattern. Discrimination was 72% in the right ear and 40% in the left ear. At the age of 71 years, he was diagnosed as

Fig. 10. Degeneration (arrow) of the utricular (U) nerve was also noted.


having leukemia and treated with Ovocin, methotrexate, Purinethol and pred-nisone with some improvement. Two months later, he developed complete rightfacial paralysis and herpetic involvement of the right auricle and soft palate. A hearing test at this time revealed bilateral sensorineural hearing loss whichwas worse than before. He died of leukemia 2 months later.

Histopathology of the TB: Postmortem Time 4 h. In the right TB, the cen-tral part of the FN in the meatus of the internal auditory canal (IAC) was nor-mal. However, there was a gradation over a 5-mm segment from normal nerveto total degeneration (fig. 17). The FN demonstrated a change from normal togranular degeneration and finally absence of all axons except the sensory bun-dle at the distal end of the IAC. The GG had a large number of satellite cells butno degenerated ganglion cells (fig. 18). There was a severe loss of cochlear neu-rons with only 5% remaining. The hair cell population in the organ of Corti wasnormal. There was moderate degeneration of all cristae ampullares. The macu-lae of the utricle and saccule showed advanced atrophy with loss of hair cells.

Fig. 11. The MG (M) contained several degenerated ganglion cells (arrows) sur-rounded by a heavy infiltrate of satellite and inflammatory cells. F � FN.

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Vestibular neurons to the cristae of superior division canals were markedlydegenerated with some preservation of innervation to the maculae (fig. 19).

In the left TB, the FN and GG were normal. There were several degeneratedneurons in the MG (fig. 20) but none in the GG. There was a severe loss of spi-ral ganglion cells with only 5% of neurons remaining, and the organ of Cortiwas normal. The vestibular sense organs and ganglion were normal.

Fig. 12. There were no degenerated ganglion cells in the GG of case 2.

Fig. 13. a Low-power view of the nerves in the internal auditory canal. There is markedswelling of the FN (F) proximal to the meatal foramen. V � Vestibule; C � basal turn of thecochlea. b The MG (M) is located in the edematous segment of the FN. V � Vestibular nerve.


Fig. 15. The MG contained some degenerated ganglion cells and many satellite andinflammatory cells (arrows).

Fig. 14. The GG in case 3 contained normal ganglion cells and satellite cells.

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Discussion

It is generally accepted that IFP (Bell’s palsy) is an inflammatory neuritiscaused by the herpes simplex or herpes zoster viruses [1–10]. However, therehave been reports associating Epstein-Barr [31, 32], mumps [33] and cytome-galic inclusion virus [34] with IFP. The NT viruses gain access to cell bodies ofsensory neurons by entering nerve endings at an epithelial surface followed byretrograde transport to the cell body. It has been assumed that the GG repre-sented the site of accumulation of the virion responsible for the inflammatoryneuritis in IFP since HSV and varicella-zoster virus DNA has been recoveredfrom the GG of patients with IFP [14] and herpes zoster oticus. The motor paraly-sis has been assumed to be a result of reaction to the virus protein. TB of patientswith a recent onset of IFP (1–2 weeks) demonstrate fragmentation, swelling and degeneration of FN axons, degeneration and phagocytosis of myelin andlymphocytic infiltration of FN bundles [35–37].

The TB from a patient 10 years after incomplete recovery of facial functionrevealed a partial loss of axons beginning in the IAC segment of the FN and progressing with severity toward the mastoid segment [37]. The IAC location ofFN degeneration in this TB as well as the TB from herpes zoster oticus (table 2)

Fig. 16. Focal axonal degeneration (arrow) in the vestibular nerve (V) was located nextto the nervus intermedius (NI).


Fig. 18. The GG is normal in case 4, and the sensory portion (S) of the FN is intact.

Fig. 17. a Case 4. Low-power view of the nerves in the IAC in a case of herpes zosteroticus. There is degeneration of all the nerves in the canal. The central portion of the FN (F)is normal but degenerated in the IAC (*). b A higher-power view shows the gradation fromnormal (F) to degenerated (*) FN.

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suggests the meatal segment of FN as the primary focus of infection. The pres-ence of degenerated ganglion cells in the MG rather than the GG and therepeated observation that early enhancement within the IAC is recorded on MRIin IFP point toward the MG as the initial site of viral accumulation. The patternof axonal loss beginning in the IAC segment of the FN supports the concept ofa demyelinating autoimmune response to the virion in the MG cells [12, 13].The location of early MRI enhancement in the meatal FN segment also indicatesthat the initial site of viral ganglionitis in IFP is the MG.

Fisch and Esslen [17] provided the first description of segmental involve-ment of the FN in IFP. During surgical exposure of the FN in the IAC and thelabyrinthine facial canal, they noted swelling and increased vascularity of themeatal FN segment. They interpreted the swelling to reflect blockage of axo-plasmic flow by a constriction at the entrance to the labyrinthine facial canal.Decompression of the labyrinthine canal was felt to be critical for the success-ful treatment of IFP.

More than a decade later, MRI studies of FN in IFP (table 1) describedlocalized enhancement of the FN in the IAC as characteristic of IFP. The location

Fig. 19. Vestibular ganglion (VG) cells were enucleated and pale. F � Degenerated FN.


and sequential development of FN enhancement in our case report are typical ofIFP. With increased time after the onset of facial paralysis, enhancement of moredistal portions of the FN usually occurs. Pooling of gadolinium in dilated vesselssurrounding [30] and within the FN [38] in the tympanic and mastoid portions ofthe fallopian canal is likely responsible for delayed enhancement in the distalsegments of the facial canal. The initial location of virus infection may spreadfrom the MG to the GG along the nervus intermedius. The characteristic lym-phocytic infiltrate between nerve bundles typifies a viral infection. The recoveryof viral DNA from the geniculate region in IFP is not contradictory.Degeneration of vestibular neurons adjacent to the MG accounts for the occur-rence of vestibular symptoms in patients with IFP [18, 39–43].

Enhancement of the meatal FN in IFP is dependent on several factors:(1) timing of the MRI; early in the course of the paralysis (within 7 days of

onset), it is likely that only the initial focus of inflammation would be enhanced;

Fig. 20. The contralateral FN (F) and MG (M) contained a few degenerated ganglioncells (arrow).

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enhancement is thought to be caused by pooling of contrast in the area withincreased vascularity and edema;

(2) the size of the MG is responsible not only for enhancement but also forthe paralysis; the virus load is dependent on the number of ganglion cells containing virus; the MG may be as large, or larger than the GG in almost 20%of TB; in the remaining 80%, although the MG is small, enhancement may beincreased because of spread of virus to the adjacent vestibular ganglion; theincidence of vertigo in patients with IFP and herpes zoster oticus is caused byviral involvement of the vestibular ganglion;

(3) the technique of MRI can increase enhancement in the meatal FN seg-ment; in the early studies that used a 0.5-tesla unit, FN enhancement was lowcompared to the more recent studies using a 1.5-tesla unit as the magnet source(table 1).

Degeneration was seen in the MG (or meatal segment) of the FN in 5 of 6TB associated with facial paralysis. In none of the 6 TB were degenerated gan-glion cells found in the GG. Degeneration of the vestibular nerve or ganglionwas found in 4 out of the 6 TB. In 2 TB, marked swelling of the FN was seenproximal to the meatal foramen. This swelling is at the point where the inflam-matory response of the FN and the MG would be constricted at the meatal fora-men. Although the MG could not be identified in the TB of herpes zoster oticusbecause of complete destruction of the FN, the FN was normal proximal to themidportion of the IAC. These findings indicate that the focus of FN degenera-tion was located in the meatal segment of the FN, near the degenerated vestibu-lar ganglion. This pattern of degeneration is consistent with pathology located at the MG.

In addition to virus load in the MG, virus strain and host resistance are fac-tors in determining the severity of infection. In most (80%) FN, the MG is verysmall, and in 20% of TB the MG is large enough to produce an inflammatoryfocus that can be detected on MRI. It is possible that the lack of FN enhance-ment on MRI series in IFP (table 1) represents those FN where the MG is verysmall (fig. 10). Spread of virus to the adjacent vestibular ganglion may be respon-sible for vestibular symptoms. The TB (patient A.B., table 2) with resolved IFPdemonstrated that vestibular afferent neurons nearest to the FN were degener-ated while those (otolith organs) farthest from the FN were intact. This patternof degenerative changes in IFP follows spread of virus from the MG to thevestibular ganglion.

The absence of meatal FN enhancement may have prognostic value indetermining the outcome in IFP. In 2 series [25, 27] of patients, those with no FNenhancement usually experienced a satisfactory outcome. In the series of Murphyand Teller [25], 6 of the 7 patients with no enhancement exhibited grade I recov-ery while 1 had a grade VI/VI outcome. Of 9 patients with no FN enhancement


in Engstrom et al. [29], 3 patients with no enhancement had the lowest electro-neurographic values at the initial clinical and MRI examination.

Certain incidence features of IFP are explained by the biologic characteris-tics of the herpes virus family. After retrograde transport, the NT viruses havethe ability to assume a latent state within the sensory ganglion cell bodies. Inresponse to external stressors or lowered immune states, the virus may reacti-vate and replicate leading to the clinical manifestations. Surgical stress is capa-ble of reactivating latent virus in facial nerve ganglion cells producing palsy.Bonkowsky et al. [44] investigated 5 of 7 ipsilateral delayed facial palsies whichoccurred in over 1,800 uncomplicated middle ear procedures. They detectedHSV-1 genome with PCR in 4 out of the 5 patients. Furthermore, the mean anti-body titer (IgG) was higher than in a control group with herpes labialis. A highincidence (80%) of subclinical contralateral facial neuropathy has been reportedin patients with early IFP [45]. This high incidence of subclinical bilaterality isconsistent with a viral etiology for the neuropathy.

A familial incidence of IFP has been recorded in several reports [3, 46, 47].This suggests a genetic influence on the anatomical substrate that determines anindividual’s susceptibility to IFP. Sensory systems as well as some motor nervesdepend on neurotropins to regulate the size (in number of neurons) they assumefollowing the programmed death of excess neurons in the developing neonatalnervous system. Brain-derived NT factor and neurotropin 3 have been shown inknockout mice to determine the size of the GG [48, 49]. The relative proportionsof contributions from the GG and MG in human TB are compatible with aninheritance model. Neurotropins could regulate a large MG in several familymembers allowing a large virus load sufficient to cause IFP after exposure toherpes simplex or varicella-zoster virus. A familial occurrence of IFP may alsobe related to intimate exposure to the causal viral agent.

Conclusion

Clinical, radiologic and pathologic observations support the contentionthat the MG of the FN represents the primary location of the viral inflammationresponsible for IFP. The term ‘meatal ganglionitis’ may be used to designate thispathologic correlate in IFP.

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30 Gebarski S, Telian S, Niparko J: Enhancement along the normal facial nerve in the facial canal:MR imaging and anatomic correlation. Radiology 1992;183:391–394.

31 Grose C, Heule G, Feorlino PM: Primary Epstein-Barr virus infections in acute neurologic diseases.N Engl J Med 1975;292:392–395.

32 Michel RG, Pope TH, Patterson CN: Infectious mononucleosis, mastoiditis and facial paralysis.Arch Otolaryngol 1975;101:486–489.

33 Beardwell A: Facial palsy due to mumps virus. Br J Clin Pract 1969;23:37–38.34 Djupesland G, Berdal P, Johannessen T, Degre M, Stien R, Skrede S: Viral infection as a cause of

acute peripheral facial palsy. Arch Otolaryngol 1976;102:403–406.35 Proctor B, Corgill D, Proud G: The pathology of Bell’s palsy. Trans Am Acad Ophthalmol

Otolaryngol 1976;82:70–80.36 Liston S, Kleid M: Histopathology of Bell’s palsy. Laryngoscope 1989;99:23–26.37 Schuknecht HF: Pathology of the Ear, ed 2. Philadelphia, Lea & Febiger, 1993, pp 330–331.38 Balkany T, Fradis M, Jafek B, Rucker N: Intrinsic vasculature of the labyrinthine segment of the

facial nerve – Implications for site of lesion in Bell’s palsy. Otolaryngol Head Neck Surg1991;104:20–23.

39 Aschan G, Stahle J: Vestibular neuronitis. J Laryngol Otol 1956;70:497–511.40 Pfaltz C: Diagnose und Therapie der vestibularen Neuronitis. Pract Otorhinolaryngol 1955;17:

454–461.41 Philipszoon AJ: Nystagmus and Bell’s palsy. Pract Otorhinolaryngol 1962;24:233–238.42 Lämmli K, Fisch U: Vestibular symptoms in idiopathic facial paralysis. Acta Otolaryngol (Stockh)

1974;78:15–18.43 Rauchbach HE, May M, Stroud J: Vestibular involvement in Bell’s palsy. Laryngoscope 1975;85:

1396–1398.44 Bonkowsky V, Kochanowski B, Strutz J, Pere P, Hosemann W, Arnold W: Delayed facial palsy fol-

lowing uneventful middle ear surgery: A herpes simplex virus type I reactivation? Ann Otol RhinolLaryngol 1998;107:901–905.

45 Safman BL: Bilateral pathology in Bell’s palsy. Arch Otolaryngol 1971;93:55–57.46 De Santo LW, Schubert HA: Bell’s palsy, ten cases in a family. Arch Otolaryngol 1969;89:

700–702.47 Willbrand JW, Blumhagen JD, May MM: Inherited Bell’s palsy. Ann Otol Rhinol Laryngol 1974;

83:343–346.48 Ernfors P, Lee KF, Jaenisch R: Mice lacking brain-derived NT factor develop with sensory deficits.

Nature 1994;368:147–150.49 Farinas I, Jones KR, Backus C, Wang Y, Reichardt L: Severe sensory and sympathetic deficits in

mice lacking neurotrophin-3. Nature 1994;369:658–661.


Vestibular Neuronitis: A ViralNeuropathy


Vestibular neuronitis (VN) or neuritis has long been regarded as an inflam-matory lesion of the vestibular nerve responsible for recurrent vertigo withouthearing loss. The clinical picture described by Nylen [1], Dix and Hallpike [2],Lumio and Aho [3] and others [4–10] was a sudden onset of acute vertigo, with-out auditory symptoms, with resolution over days. In many patients, an upperrespiratory illness or infection (sinusitis) preceded the appearance of vertigo,and affected patients often appeared in clusters during a season with a high incidence of respiratory illness. The association with sinusitis was so strong thatone author [9] identified a subset of patients with vestibular symptoms andsinusitis. Viral antibody titers were also elevated in VN [11]. It was appreciatedthat recurrent vertigo could have a shorter duration (hours or minutes) in somepatients. The clinical feature differentiating VN from Ménière’s disease is theabsence of hearing loss, and the diagnosis of VN is dependent on a unilateral orbilateral vestibular deficit. Although the strict criterion for a diagnosis of VNrequired total or subtotal loss of vestibular function, it was recognized that lessvestibular hyposensitivity was possible in VN. Furthermore, some patients witha significant vestibular loss on the initial examination eventually recoveredvestibular function on the follow-up evaluation.

Several temporal bone (TB) reports have described total or subtotal degener-ation of the vestibular nerve in VN [12–14]. The auditory sense organ and neu-rons were normal or near normal. Description of fibrosis in the perilymphaticspace surrounding the ampullary ends of the semicircular canals supported aninflammatory nature of the lesion [12]. Enhancement of the vestibular nerve in the internal auditory canal with contrast-enhanced MRI has been reported inpatients with VN [15]. Such focal enhancement may have been interpreted asvestibular schwannoma in the past. However, follow-up imaging of the enhanc-ing portion of the vestibular nerve demonstrated resolution in other patients.

Chapter 4

Estimation of vestibular nerve degeneration in patients with VN, Ménière’sdisease, benign paroxysmal positional vertigo and other recurrent vestibulopathieswas reported in a series of 51 TB with an axonal degeneration pattern of bundlesof fibers in the vestibular nerve trunk [16]. Clusters of degenerated ganglioncells were seen in some of the vestibular ganglia (VG). The meatal ganglion(MG) of the facial nerve adjacent to the vestibular nerve contained degeneratingganglion cells in almost all of the TB. Measurement of the axonal degenerationwas based on a point-counting technique which strictly measured focal areas ofdegenerating fibers and therefore underestimated the extent of pathology sincesmaller fascicles and individual fibers were overlooked with this technique ofmeasurement. The control that such MG and vestibular nerve degeneration was not related to age, sex, artifact in TB acquisition or labyrinthine disease was provided by 24 TB that were matched for age, sex and presence of otherlabyrinthine disease. These TB did not show focal axonal degeneration in thevestibular nerve nor degenerated ganglion cells in the MG.

The view that VN presents only as a single attack of vertigo is probably toorestrictive. Frequently VN can manifest itself as recurring attacks of vertigowithout hearing loss occurring anytime in adult life and usually preceded by astressful event such as sinusitis, upper respiratory tract infection or idiopathicfacial paralysis [12]. Although hearing loss is usually not part of this clinicalpicture, some patients may complain of tinnitus and fullness in the affected ear.A decreased vestibular response (�25%) at some point in the patient’s evalu-ation is necessary to identify the affected ear.

The TB described in this report (table 1, see Appendix) is compared to 20 TB that were age and sex matched but without a history of vertigo (table 4,see Appendix). Degeneration in the vestibular nerve and the MG of the vestibu-lopathic TB suggests a viral neuropathy. Morphologic changes in the facial andvestibular nerves will be described in this report. Other findings recorded intable 1 are discussed in a later chapter.


TB Specimens

Twenty TB had been fixed in 10% formalin, decalcified and embedded in celloidin,then horizontally sectioned at 20 �m and stained with hematoxylin and eosin. Twelve of theseTB had a recorded history of vertigo without hearing loss. Although a history of vertigo wasnot recorded in the remaining 8 TB, degenerative changes in the MG and vestibular nervewere similar to those found in the 12 TB with a vertigo history. Twenty TB from patientswithout vestibular symptoms and representing an age- and sex-matched group were alsoexamined for degeneration in the MG, the VG and the spiral ganglion.

Vestibular Neuronitis: A Viral Neuropathy 55

Gacek/Gacek 56

The percentages of degeneration in the MG, VG and spiral ganglia were estimated in thefollowing way:

(1) the total number of degenerated ganglion cells in all sections that contained the MGwas divided by the total number of ganglion cells (both normal and degenerated) in the ganglion; this fraction was used to compute the percentage of degenerated ganglion cells inthe MG;

(2) vestibular nerve and VG degeneration was estimated using 20% to represent eachvestibular nerve branch; if the superior division was degenerated, with the exception of theutricular nerve, it was computed as 40% degenerated; if peripheral branch degeneration wasnot present, the fraction of the total vestibular nerve trunk area occupied by focal axonaldegeneration was estimated and used to compute the percentage of degeneration;

(3) spiral ganglion cell loss was estimated similar to the approach used by previousinvestigators [12]; in this way, the percentage of ganglion cells in Rosenthal’s canal of thecochlear turns was recorded.

Degeneration in two additional nerve bundles of the TB was assessed and recorded.(1) Degeneration in the tympanic nerve (Jacobson’s nerve) was recorded in sections

of the TB that included the promontory and round window niche. The tympanic nerve wasjudged to be normal or degenerated.

(2) The vestibulocochlear anastomosis was identified as it emerges from the saccularganglion in the internal auditory canal. It was judged intact or degenerated.

The presence of deposits in the labyrinthine sense organs was also determined in theseTB; criteria for their identification and significance are described in chapter 8.

Illustration

The histories and histopathologic findings in 2 TB are presented to illustrate early andadvanced VN.

Results

TB Specimens

Table 1 (Appendix) summarizes the morphologic findings in 20 TB with adiagnosis consistent with VN. Twelve of these 20 donors had a history of vertigoprior to the acquisition of their TB. In 3 individuals, the diagnosis of VN was made prior to death. In the remaining 9 patients with a vertigo history, nospecific vestibular syndrome was identified. All but 1 of these 20 TB revealeddegeneration in the MG, and all 20 TB contained focal axonal degeneration inthe vestibular nerve. In case 10, the entire vestibular nerve and its branches weredegenerated. This TB has been reported previously [12]. In 15 TB, degenerationof the spiral ganglion was either minimal or limited to the basal turn, and con-sidered consistent with the patient’s age and occupation. In 3 TB, the apical turn degeneration was significant. In 2 TB, severe degeneration of the spiral


ganglion was felt to be related to the pathologic process. The tympanic branch of the ninth nerve was normal in 12 TB and partially degenerated in 8. The presence of tympanic nerve degeneration did not correlate with the severity ofthe vestibular nerve degeneration.

In 20 TB without a history of vertigo, evidence of degeneration was foundin the MG of 1. No degeneration was found in the vestibular ganglia or nervesof all 20 TB. The spiral ganglion was normal or degenerated only in the basalturn in all 20 TB. The tympanic nerve was normal in 16 TB and partially degenerated in 4 TB.

Illustration

Two TB illustrate the morphologic changes in mild and severe VN.

Case 1: 87-Year-Old FemaleAt the age of 84 years, the patient experienced a sudden episode of vertigo

throwing her to the right which was accompanied by nausea and vomiting.Although improved the following day, she complained of unsteadiness whenwalking. Audiometric studies revealed a bilateral sensorineural hearing loss.Speech discrimination was 92% on the right and 64% on the left. Caloricresponses to 10 ml of ice water were absent on the right and normal on the left.Positional and turning tests were negative. The Romberg test showed a tendencyto fall to the right. She still exhibited unsteadiness when walking at the age of85 years. A hearing test at the age of 85 years showed discrimination at 72% onthe right and 80% on the left. At the age of 87 years before her death frommyocardial infarction, she still complained of unsteadiness.

Histopathology: Right TB, Postmortem Time 12 h. There was severe atrophyof the spiral ligament in the apical half of the cochlea. Although the organ ofCorti showed clumping, hair cells were present throughout. There was a 50%loss of cochlear neurons in the basal turn. The cochlear and vestibular nerveshad been avulsed from the internal auditory canal. The MG in the facial nervecontained several degenerated neurons and intact neurons surrounded by satel-lite cells (fig. 1). The lateral and superior canal cristae were atrophic, and theirinnervation was completely degenerated (fig. 2). The sense organs and inner-vation for the utricle (fig. 3), saccule (fig. 4) and the posterior canal (fig. 5)were normal.

Case 2: 92-Year-Old FemaleThis TB was reported by Schuknecht and Kitamura [12] to illustrate VN.

However, the histopathology in the VG was not described in that report. At the

Fig. 2. Vestibular neurons to the lateral canal (LC) crista were completely degenerated(arrow).

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Fig. 1. Case 1. There were several degenerated ganglion cells (arrows) in the MG of thefacial nerve.


Fig. 3. The utricular nerve (arrow) and macula (U) were normal.

Fig. 4. The saccular macula (S) and its nerve supply (arrow) were normal.

Gacek/Gacek 60

age of 72 years, the patient fell in her cabin while on a cruise ship and remainedunsteady for several weeks following this episode. She walked with a broadbase and was unsteady on turns. Audiometric studies revealed a bilateral sen-sorineural hearing loss. The unsteadiness increased over the next year until shesuddenly experienced severe vertigo with nausea and vomiting which was docu-mented by a spontaneous right beating nystagmus. The vertigo subsided after 3 days. Bithermal caloric tests revealed a marked directional preponderance tothe right. By the age of 80 years, she continued to have a constant feeling of unsteadiness and several episodes of falling at home. Caloric tests revealed a1-min 49-second response on the right and no response on the left. Repeat hear-ing tests showed 64% speech discrimination on the left and 42% on the right.Between the ages of 80 and 92 years, she continued to experience repeatedfalling episodes; while in a nursing home her health deteriorated, and she diedat the age of 92 years from cardiac and renal failure.

Histopathology: Left TB, Postmortem Time 16 h. Except for atrophy in asmall segment of the extreme basal end of the cochlea, the organ of Corti waspresent with hair cells. A loss of cochlear neurons of 80% at the 11-mm location, a 50% loss from 11 to 16 mm and a normal amount in an apical directionwas consistent with her age. Mild atrophy of the stria vascularis was present.There was almost complete degeneration of nerve fibers to the lateral and superior

Fig. 5. The posterior canal crista (PC) and its nerve (arrow) were normal.


canal cristae (fig. 6) as well as the utricular macula (fig. 7). The innervation to the saccular macula (fig. 8) and the posterior canal crista (fig. 9) was intact.The vestibular nerve branches had been avulsed from the cribrose portion of the bony labyrinth, but the VG was located in the proximal end of the internalauditory canal. The VG showed a chronic inflammatory process with satelliteand inflammatory cells surrounding ganglion cells which were in various stagesof degeneration (fig. 10). In some areas of the ganglion where neurons were

Fig. 6, 7. Case 2. There was almost complete degeneration of innervation (arrows) tothe superior division sense organs. LC � Lateral canal crista; U � utricular macula.

Fig. 8, 9. Case 2. The innervation to the inferior division sense organs (arrows) wasintact. S � Saccular macula; PC � posterior canal crista.

Gacek/Gacek 62

Fig. 10. Case 2. The VG showed ganglion cells in various stages of degeneration(arrows) surrounded by an increased number of satellite and inflammatory cells. The solidmaterial on the left may represent plaque formation by the virus.

absent, a dense blue matrix had replaced the ganglion. There were also numerousspherical masses which had a laminated appearance. The MG of the facial nervecontained several degenerated ganglion cells replaced by a pale collagen-likesubstance (fig. 11).

Discussion

The morphologic changes in 20 TB consisted of degenerated ganglion cellsin the MG and focal axonal degeneration in the vestibular nerve and VG. Exceptfor 1 TB (case 10) with extensive vestibular nerve degeneration, the pattern offocal degeneration in the vestibular nerve represents projections from clustersof ganglion cells in the VG. Focal axonal degeneration had been described intrigeminal nerve zoster by Denny-Brown et al. [17]. Degenerated ganglion cellssurrounded by normal ones in the MG are explained by a pathology specific for neurons. Ischemic injury is not cell specific enough to preserve adjacentneurons. In none of the TB were degenerated ganglion cells found in the genic-ulate ganglion. The absence of degenerated cells or axons in the facial and


vestibular nerves in the control group of TB supports the conclusion that thesechanges are not age, sex or peripheral pathology related. Furthermore, in the TBwith extensive degeneration of vestibular nerve branches (case 10), the VG contained histologic changes similar to those described in animal models of herpetic ganglionitis. Increased numbers of satellite and inflammatory cells surround intact and degenerated ganglion cells. The basophilic stained groundsubstance between ganglion cells may be similar to plaque formation producedby viruses.

It is not surprising to see enhancement of the VG on MRI where pooling ofcontrast material in the vasculature of an inflamed ganglion creates a localizedenhancement [15, 18]. The association of vertigo with the development of VN,Ménière’s disease or benign positional vertigo following idiopathic facial paralysis may be based on the proximity of the VG to the MG [19]. This prox-imity and, in some TB, the contiguity of the MG and VG may be responsible forvirus spread from the MG to the vestibular nerve earlier in life when latency isestablished.

Reactivation of latent virus in the MG and adjacent VG acquired early inlife is an expected sequela of neurotropic viruses (i.e. herpes simplex virus, HSV)which have the ability to travel bidirectionally in sensory ganglion cells [20].Since this flow is strain dependent [21–23] flow toward the brainstem accountsfor the absence of hearing loss and occasional central signs in VN [24]. Thedemonstration of HSV nucleic acids in a large proportion of human geniculate

Fig. 11. The MG (M) contained several degenerated ganglion cells replaced by collagen(arrow). F � Facial nerve.

Gacek/Gacek 64

ganglia and VG provides molecular evidence of a reactivated HSV infection ofthe vestibular nerve [25]. If the HSV strain follows anterograde flow in thevestibular nerve (toward the brain), hearing is preserved (fig. 12). Such antero-grade flow may carry viral products transsynaptically to second-order neuronsin the brainstem. Central nervous system signs have been described in patientswith VN [24]. Arbusow et al. [26] have demonstrated HSV-1 bilaterally in theTB and brainstems of 5 patients.

Clinical findings in patients with VN are dependent on the amount andlocation of viral involvement of the VG. Infection of ganglion cells supplyingthe cristae is responsible for rotatory vertigo while the neurons innervatingotolith sense organs (i.e. the utricular macula) will give rise to ataxia or dropattacks. It is not unusual for the level of vestibular sensitivity to change depend-ing on virus activity [27]. Therefore, finding an initially decreased vestibularresponse following caloric stimulation which recovers to a normal level follow-ing resolution of vestibular symptoms is not unexpected. When a sufficientnumber of VG cells have degenerated, especially in the superior vestibular divi-sion, a decreased response can be recorded following caloric stimulation. In thepresent series there were 4 patients in whom caloric testing had been performedprior to death. A significantly decreased response (none or decreased) wasrecorded in all 4 patients. Degeneration of the VG was estimated at 40% in 3 and90% in 1 of these TB. The 40% degeneration represents affected VG cells inner-vating the lateral and superior canal cristae which are located adjacent to theMG of the facial nerve.

Stapes

RW

U

S

VGBrainstem

VestibularNuclei

Fig. 12. Schematic of anterograde virus flow after reactivation in the VG. This direc-tion of virus flow avoids hearing loss but may account for passage of virus to second-orderneurons in the vestibular nuclei. U � Utricle; S � saccule; RW � round window.

In some patients with recurrent vertigo and normal hearing, vestibularexamination (electronystagmography) is normal because there is insufficientdegeneration of vestibular neurons to produce a diminished response usingpresent criteria of 25–30% reduced response (compared to the intact side).Perhaps the current criteria for defining a vestibular weakness should be recon-sidered. Differences of less than 25% in the vestibulocular response may reflectminimal VG degeneration. Since it is possible with MRI to demonstrate aninflammatory process in the VG, neuroimaging should also be considered partof the vestibular examination.

Conclusion

Degeneration of the VG initially in clusters of ganglion cells which mayeventually lead to widespread ganglion cell loss by neurotropic viral reactivationis similar to the axonal degeneration pattern typical of herpes zoster trigeminus.Molecular studies amplifying HSV DNA from vestibular nerves in human TBsupport a viral etiology of VN. The close association of the VG and MG togetherwith the frequency of degenerated neurons in these ganglia suggests that theportal of entry of the virus may be over the greater superficial petrosal nerve.

References

1 Nylen C: Some cases of ocular nystagmus due to certain positions of the head. Acta Otolaryngol(Stockh) 1924;6:106–123.

2 Dix M, Hallpike C: The pathology, symptomatology, and diagnosis of certain common disordersof the vestibular system. Ann Otol Rhinol Laryngol 1952;61:987–1016.

3 Lumio JS, Aho J: Vestibular neuronitis. Ann Otol Rhinol Laryngol 1964;74:264–270.4 Aschan G, Stahle J: Vestibular neuritis. J Laryngol Otol 1956;70:497–511.5 Hart C: Vestibular paralysis of sudden onset and probably viral etiology. Ann Otol Rhinol Laryngol

1965;74:33–47.6 Harrison M: Epidemic vertigo: Vestibular neuronitis, a clinical study. Brain 1962;85:613–620.7 Merifield DO: Self-limited idiopathic vertigo (epidemic vertigo). Arch Otolaryngol 1965;81:

355–358.8 Pedersen E: Epidemic vertigo: Clinical picture, epidemiology, and relation to encephalitis. Brain

1959;82:566–580.9 Coats A: Vestibular neuronitis. Acta Otolaryngol Suppl (Stockh) 1969;251:1–32.

10 Clemis JD, Becker GW: Vestibular neuronitis. Otolaryngol Clin North Am 1973;6:139–155.11 Shimizu T, Sekitani T, Hirata T, Hara H: Serum viral antibody titer in vestibular neuronitis. Acta

Otolaryngol Suppl (Stockh) 1993;503:74–78.12 Schuknecht HF, Kitamura K: Vestibular neuritis. Ann Otol Rhinol Laryngol 1981;90(suppl 78):

1–19.13 Nadol JB: Vestibular neuritis. Otolaryngol Head Neck Surg 1995;112:162–172.14 Baloh RW, Lopez I, Ishiyama A, Wackym P, Honrubia V: Vestibular neuritis: Clinical-pathologic

correlation. Otolaryngol Head Neck Surg 1996;114:586–592.15 Fenton JE, Shirazi A, Turner J, Fagan P: Atypical vestibular neuritis: A case report. Otolaryngol

Head Neck Surg 1995;112:738–741.


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16 Gacek RR: The pathology of facial and vestibular neuronitis. Am J Otolaryngol 1999;20:202–210.17 Denny-Brown D, Adams RD, Fitzgerald PJ: Pathologic features of herpes zoster: A note on genicu-

late herpes. Arch Neurol Psychiatry 1949;51:216–231.18 Gacek R, Gacek M: The three faces of vestibular ganglionitis. Ann Otol Rhinol Laryngol, in press.19 Gacek R: On the duality of the facial nerve ganglion. Laryngoscope 1998;108:1077–1086.20 Meier JL, Straus SE: Comparative biology of latent varicella zoster virus and herpes simplex virus

infections. J Infect Dis Suppl 1992;166:S13–S23.21 Zemanick MC, Strick PL, Dix RD: Direction of trans-neural transport of herpes simplex virus I in

the primate motor system is strain-dependent. Proc Natl Acad Sci USA 1991;88:8048–8051.22 Card JP: Exploring brain circuitry with neurotropic viruses: New horizons in neuroanatomy. Anat

Rec (New Anat) 1998;253:176–185.23 Kuypers HG, Ugolini G: Viruses as transneuronal tracers. Trends Neurosci 1990;13:71–75.24 Silvoniemi P: Vestibular neuronitis: An otoneurological evaluation. Acta Otolaryngol Suppl

(Stockh) 1988;453:1–72.25 Arbusow V, Schulz P, Strupp M, Dieterich M, et al: Distribution of herpes simplex virus type I

in human geniculate and vestibular ganglion: Implications for vestibular neuritis. Ann Neurol1999;46:416–419.

26 Arbusow V, Strupp M, Wasicky R, Horn AKE, Schultz P, Brandt T: Detection of herpes simplexvirus type I in human vestibular nuclei. Neurology 2000;55:880–882.

27 Ohbayashi S, Oda M, Yamamoto M, et al: Recovery of vestibular function after vestibular neuronitis. Acta Otolaryngol Suppl (Stockh) 1993;503:31–34.


Ménière’s Disease: A Form of Vestibular Ganglionitis


The treatment of Ménière’s disease (MD) remains controversial because itscause is incompletely understood. Endolymphatic hydrops (EH) has beendescribed consistently as the hallmark pathology in MD [1–3]. EH has beenproduced following occlusion of the endolymphatic duct in some animal mod-els. The successful animal models are in lower mammalian forms such as theguinea pig, gerbil and chinchilla [4–7], whereas only mild or no EH develops innonhuman primates even years after obstruction of the endolymphatic duct [8].Nevertheless, the demonstration of extensive EH in the human temporal bone(TB) as well as some animal models supports the theory that ruptures of adilated membranous labyrinth result in a release of high-potassium endolymphthat is toxic to neural function in both the auditory and vestibular systems [9].However, major differences exist between human TB observations and the animalmodels of EH. Animals with experimental EH are not observed to have vertigo[4], and their TB do not demonstrate perilymphatic fibrosis in the vestibule andcochlea as seen in human TB specimens from MD patients [10]. In addition,other features in MD such as the occasional (10–15%) loss of apical spiral ganglion cells in MD [11] as well as delayed-onset ipsilateral (IDEH) or contralateral (CDEH) hydrops are difficult to explain on the basis of EH alone [12–14].

A number of investigators have suggested that the labyrinth prior to theonset of MD is predisposed to the development of EH as a result of a stressfulevent [15]. These include head trauma, infections of the sinuses or ear andallergy. Although it is possible that the target for the transformation of a pre-disposed labyrinth is EH, no morphologic, functional or immunologic evidencehas shown that the endolymphatic sac is responsible for MD. Clinical treatmentsdesigned to relieve EH by surgical or medical approaches are equivocal in controlling symptomatic MD. It is possible that a latent viral infection of the

Chapter 5

vestibular ganglion (VG) could represent a predisposed state of the labyrinthwhich can then be triggered (activated) by various stressful events resulting inthe clinical presentation of MD.

A number of observations have suggested a viral etiology, and somereports point to the focus of pathology in the vestibular nerve or VG. However,although an elevated herpes simplex virus (HSV) antibody response is detectedin patients with MD [16–19], the latency-associated transcript (LAT) was notfound in the ganglion [20] or in the endolymphatic sac [21]. Adour et al. [22, 23]were among the first to suggest that MD is part of a polyganglionitis caused byreactivation of a neurotropic virus such as HSV following a stressor. None-theless, the lack of morphologic evidence in the vestibular nerve of MD TB aswell as the persuasive features of the EH theory prevented acceptance of theviral ganglionitis theory in MD. Palva et al. [24] investigated the presence ofviral particles in the VG excised from patients with MD using transmission elec-tron microscopy. Structures resembling viral organisms were identified butcould not be differentiated from similar structures in normal vestibular nerves.Attempts to amplify viral DNA in vestibular nerves excised from MD patients[25] have been unsuccessful until recently. Pitovski et al. [26] and Rosensteinand Pitovski [27] demonstrated HSV LAT and thymidine kinase genes in VG inpatients with MD. They had previously demonstrated that HSV LAT was present in more than 70% of normal VG. These data support the concept that arecurrent neuropathy such as MD may occur in a fraction of the population thatharbor latent HSV in vestibular nerves and then may be subjected to a stressfulincident that triggers reactivation of the virus later in life.

Since MD is unique to the human species, evidence of ganglionitis shouldbe found in the TB from patients who exhibit the clinical features of the disease.Our TB collection indicates that there are morphologic changes in the TB ofMD patients similar to those from patients with vestibular neuronitis supportingthe concept of vestibular ganglionitis [28]. Similar changes were found in thevestibular nerves of patients with benign paroxysmal positional vertigo, a disorderalso frequently associated with a viral insult. A unitary concept of the patho-physiology in these three recurrent neuropathies will be discussed in a subsequentchapter.


Ten TB from 7 patients who had been diagnosed as having MD before death were studied. The TB had been fixed in 10% formalin, embedded in celloidin, sectioned in a hori-zontal plane at 20 �m thickness, and every 10th section was mounted after staining withhematoxylin and eosin. The sections were examined under the light microscope. The amount

Gacek/Gacek 68

of degeneration in the meatal ganglion and the VG were estimated according to the tech-niques described in the chapter on vestibular neuronitis. The spiral ganglion was similarlyevaluated for ganglion cell loss in various turns of the cochlea. The tympanic nerve(Jacobson’s nerve) was examined in sections at the promontory level for evidence of degen-eration. Additional morphologic changes found in TB with MD were also recorded. Thesewere: the presence of EH, fibrosis in the vestibular cistern, outpouchings of the pars superiorof the membranous labyrinth and apical spiral ganglion cell loss.

The vestibulocochlear anastomosis was examined as it emerges from the saccular ganglion in all TB and was judged to be either degenerated or normal. The presence of concretions in the sense organs and associated structures of the labyrinth were recorded andmapped on a cochleogram and vestibulogram. The significance of these deposits is discussedin chapter 8.

Results

Table 2 (Appendix) includes a demographic description for the MDpatients who donated these TB. The patients with MD ranged in age from 58 to83 years. There were 5 females and 2 males in this series. Their cause of deathis listed along with the otologic diagnosis. All 10 TB contained focal axonaldegeneration in the vestibular nerve or ganglion with some measuring up to40% but most in the range of 10–20% (fig. 1). The VG cells in these TB weresurrounded by an increased number of satellite cells (more than 4 per ganglioncell) compared to the normal 1–2 satellite cells per ganglion cell in the humanvestibular nerve [29]. All but 1 TB demonstrated degenerated neurons in theMG of the facial nerve (fig. 2). In no TB were there any degenerated geniculate

Ménière’s Disease: A Form of Vestibular Ganglionitis 69

Fig. 1. a The vestibular nerve trunk carried many fascicles of degenerated axons(arrows) of similar size. b These fascicles (arrowheads) were devoid of nerve fibers and filledwith Schwann cell nuclei aligned parallel to the direction of the nerve.

ganglion cells. The spiral ganglion was judged to be normal in both TB ofpatient 3 (58-year-old male) . The other 8 TB revealed a loss of ganglion cells inthe basal turn consistent with age, and in 3 of these there was degeneration ofspiral ganglion cells in the apical region (fig. 3). All 10 TB demonstrated EH ofthe pars inferior. Three TB contained evidence of outpouchings or herniations inthe membranous wall of the pars superior of the labyrinth. These outpouchingswere located in the region of the utricular wall and/or one or more of the semicircular canal ampullary walls (fig. 4). No outpouchings were found in themembranous limb of the semicircular canals. Six TB contained fibrosis whichinterfaced a dilated saccular wall with the undersurface of the footplate (fig. 5).

The morphologic changes in the labyrinthine sense organs in MD TB willbe described in chapter 8. Degeneration of the vestibulocochlear anastomosisand the tympanic nerve is also discussed in this later chapter.

Discussion

The observations in the present study support the concept that the clinicalmanifestations and the morphologic findings in patients with MD are the result

Gacek /Gacek 70

Fig. 2. The meatal ganglion demonstrated degeneration of ganglion cells (arrows) inall but 1 TB.

of vestibular ganglionitis, probably of viral etiology. The changes in 10 TB from7 patients with MD demonstrated EH of the pars inferior along with focalaxonal degeneration in the vestibular nerves in all TB. The vestibular nervedegeneration is unique to the MD diagnosis because a series of control TB indicated that focal axonal degeneration is not related to age, sex or to a varietyof other otologic pathologies (table 4, see Appendix). Furthermore, focal degen-eration of axons has been described in herpes zoster of the trigeminal nerve[30]. The concept of VG pathology in MD is supported by quantitative meas-urements of the vestibular nerve and ganglion in TB from MD. Spoendlin et al.[31] measured a decrease in both the superior and inferior VG cell count of theaffected TB compared to the unaffected control side in a single patient with MD.Tsuji et al. [32] demonstrated a significant loss of VG cells in 30 TB from 24patients with MD compared to age- and sex-matched normative data.

Six out of the 10 TB contained fibrosis in the vestibular cistern, an observation that has been reported in 15–20% of MD TB [12]. The fibrous


Fig. 3. Degeneration of apical ganglion cells (*, arrowhead) was seen in 3 TB with MD.R � Distended Reissner’s membrane.

Gacek /Gacek 72

Fig. 4. The arrow indicates outpouching in the posterior ampullary wall of a TB withMD. The asterisk indicates fibrosis in the perilymphatic compartment.

Fig. 5. A distended saccular (S) wall is attached to the undersurface of the stapes footplate (FP) by fibrous tissue (*).

tissue attachment of a dilated saccular wall to the footplate is thought to beresponsible for Hennebert’s sign in MD. This fibrosis is indicative of an inflam-matory component in MD. Outpouchings in the pars superior and a loss of apical ganglion cells were noted in 3 TB in this series. It may be significant thatthe outpouchings were located in the membranous labyrinth wall near the termination of vestibular nerve branches. It is possible that such membranouswall deformities are caused by a weakening of the membranous wall as a resultof an inflammatory process. Isolated degenerated neurons in the MG and focalaxonal degeneration in the vestibular nerve are consistent with a virus-inducedganglion cell lesion.

As described in the previous chapter and the chapter on the biology of neurotropic viruses, the process of entrance of a neurotropic virus into the sensory nerve takes place earlier in life, providing that complementary recep-tors in the plasma membrane of the sensory neuron attract glycoproteins in theviral envelope responsible for attachment and invasion of the sensory neuron bythe virus [33, 34]. After active infection, the virus may subside into a latent statewithin the nucleus of the ganglion cell where it resides for decades waiting to bereactivated at a later point in life [35]. The focal vestibular axonal degenerationfound in the TB of this series lends support to earlier reports of fibrosis [36],degeneration as well as loss of VG cells [31, 32] in TB with MD indicating a VGlocation for the cause of MD. Rosenstein and Pitovski [27], using PCR and insitu PCR, detected HSV LAT in over 70% of the VG from normal adults. This high incidence agrees with longitudinal studies showing a majority of thepopulation having elevated HSV antibody levels with increased age. The Pitovskigroup also used the technique of in situ reverse-transcriptase PCR to detect andlocalize HSV-1, LAT and thymidine kinase transcript gene sequences in vestibularnerves excised from patients with MD [26]. The thymidine-kinase- and LAT-positive VG cells are strong evidence of a viral infection in patients with MD.

While the absence of auditory symptoms in vestibular neuronitis isexpected in the presence of vestibular ganglionitis, the association of auditorydeficits with recurrent vertigo in MD seems incompatible with vestibular ganglionitis. However, recent evidence on virus behavior offers a basis for thisparadox [37–40]. Viruses such as the McIntyre strain of HSV flow in a retro-grade direction (toward the periphery) while the H 129 strain of HSV flows inan anterograde direction (toward the brain). Therefore, reactivation of a latent H129 strain of virus in the VG will cause the flow of toxic nucleic acids and virusparticles toward the brainstem where it may even cause central features if infectivity is carried transsynaptically to the vestibular nuclei. However, if thelatent vestibular ganglionitis is caused by the McIntyre strain of HSV, the flowof nucleic acids and viral toxicity is over vestibular nerve branches toward thelabyrinth (fig. 6). This retrograde release of nucleic acids and toxic proteins into


the perilymphatic space may be responsible for inciting fibrosis in the vestibu-lar cistern where the utricular nerve is generously surrounded by perilymph.Retraction of vestibular fibrosis could displace the saccular wall to the undersurface of the footplate. The outpouchings typically found in the utricularand ampullary walls of the pars superior are located in areas where nucleic acidrelease would be greatest and could weaken the structure of the membranouswall resulting in herniations or outpouchings.

The occurrence of low-frequency sensorineural hearing loss and loss ofapical ganglion cells is best explained by a migration of nucleic acid and viralprotein toxicity from the vestibular cistern up the scala vestibuli and through thehelicotrema to contact the apical ganglion cells by penetrating the undersurfaceof the osseous spiral lamina in the apical turn [12]. It has been shown in patientswith vestibular neuronitis or MD that enhanced MRI can demonstrate high signal enhancement in the region of the VG simulating eighth-nerve tumor butactually representing an increased blood flow through the inflamed ganglion[41]. Specimens of VG excised from patients with MD with an enhancing lesionin the auditory canal have shown pathology that is consistent with vestibularganglionitis [41].

Vestibular ganglionitis provides an explanation for the delayed presentationof EH. In both IDEH and CDEH, the unilateral profound hearing loss occurs inchildhood (about the age of 4 years) as a result of viral labyrinthitis, mastoidsurgery, head injury or influenza, while the onset of the late phase is delayedabout 20 years [13, 14]. In IDEH, the late phase is characterized by episodic

Gacek /Gacek 74

Stapes

RW

U

S

VGBrainstem

Vestibularnuclei

Fig. 6. Schematic retrograde virus flow from the VG. Release of toxic viral productsinto the perilymphatic space causes fibrosis in the vestibule (stippled area) and toxicity toapical spiral ganglion cells. U � Utricle; S � saccule; RW � round window.

vertigo caused by EH in the deaf ear, while in CDEH the late phase pre-sents with a fluctuating low-frequency sensorineural hearing loss associatedwith pressure and tinnitus. Episodic vertigo occurs in about half the patientswith CDEH.

A prominent feature of the pathology in delayed EH is the incidence ofreduced vestibular function in both ears. Schuknecht’s series of 31 patients withIDEH and 31 with CDEH revealed that 11 of the 31 CDEH patients showed profound vestibular loss in the deaf ear, but only 4 of the IDEH had a similarloss in the deaf ear [12]. Furthermore, there was a profound loss of vestibularfunction in 12 of the opposite ears in CDEH but in only 1 of the IDEH cases.Abnormal vestibular responses in the deaf and contralateral ears were even moretelling. The deaf ear in IDEH revealed a reduced or absent vestibular responsein 25 cases, while 22 patients with CDEH had a reduced or absent response. Thecontralateral ear in CDEH revealed a normal vestibular response in 11 out of 31.These observations suggest that the event responsible for decreased vestibularfunction is severer when both ears develop EH than when delayed EH isrestricted to the deaf ear.

Recurrent viral activation from a latent state in the VG is a suitable hypo-thesis accounting for the clinical expression and histopathologic features ofMD. Schuknecht [12] expressed insight toward this possibility in summarizingthe significance of the delayed forms of progressive EH: ‘Assuming that virallabyrinthitis can occur in infants as a subclinical disease that results in delayedEH, we may have an explanation for the cause of MD. Viewed in this context,the disease entity known as delayed EH becomes the missing link in under-standing the pathogenesis of Ménière’s disease.’

Recurrent vertigo is the central and most prominent symptom in MD. Yetvestibular sensitivity measured by the caloric method of provoking an ocularresponse does not follow a progressive decrease as would be expected if repeatedpotassium intoxication of vestibular nerve terminals were responsible for recur-rent vertigo. A telling report on caloric test abnormalities in MD was given byProctor [42]. One hundred twenty-two cases of unilateral MD out of more than700 patients were tested at least twice with a mean interval of 2.4 years betweentests. Canal paresis was found on the involved side in 58% of patients and on thenormal side in 19%. Complete paralysis was found in 7%. Twenty-six percent ofpatients tested more than twice showed both increases and decreases in caloricresponses. Only 1 of 8 patients examined after an acute attack showed adecreased response on the affected side. Three patients showed no differenceand 4 showed an increased response after an attack.

Two mechanisms for the development of EH have been demonstrated: (1) obliteration of the endolymphatic duct in some animals, especially theguinea pig and chinchilla, results in EH of the Passinferior because of


obstructed longitudinal flow of endolymph to the endolymphatic sac; (2) EHmay develop following the deposition of foreign proteins in the perilymph as inserous labyrinthitis [43]. A major difference in the histopathology of these 2mechanisms experimentally induced in the animal is that fibrous tissue in theperilymphatic space is lacking when the endolymphatic duct is blocked, but it is a typical feature of toxic labyrinthitis. Furthermore, outpouching in the pass superior space are not seen in the EH of animals following endolymphaticduct obstruction.

Any concept of MD must address the differences between EH in the MDpatient and the experimental animal model of EH. The absence of vertigo in the animal model of EH, together with vestibular responses in MD patientswhich do not reflect a progressive deterioration that should result from repeatedchemical paralysis weakens the theory that ruptures of the membranouslabyrinth with release of endolymph toxic to neural elements in the perilym-phatic space are responsible for balance disturbances. On the other hand,vestibular ganglionitis with repeated reactivation and release of virus into theperilymph accounts for the unpredictable recurrence of vertigo in MD. The rupture theory would be expected to produce similar episodes of imbalance. The tissue response to virus release in the perilymph may account for thehistopathologic features of MD.

A low-frequency fluctuating sensorineural hearing loss is typical of earlyMD while a flat one with no fluctuation is seen late in MD. The low-frequencythreshold pattern has been attributed to a gradient of changes in the motionmechanics of the cochlear partition produced by an increased volume ofendolymph (EH). However, a physical change in the cochlear duct does notaccount for the poor speech discrimination or recruitment which is a frequentfinding in MD. The threshold elevation should be evenly graded throughout thefrequency spectrum if it is determined by the physical characteristics of thecochlear partition. The low-frequency threshold elevation in early MD risesabruptly to a normal threshold for 1 or 2 kHz. This feature of the ascendingthreshold pattern in MD is explained by neurotoxicity of apical turn sensorineuralunits. Possible sources of neurotoxicity are potassium-dominated endolymphreleased through a rupture in the membranous labyrinth or virus expressed fromterminal vestibular nerve branches (i.e. utricular nerve) into the perilymph.Perilymph fibrosis is a more likely response to an inflammatory toxin than to anionic one. After traveling up the scala vestibuli from the basal to apical turnthrough the helicotrema, these neurotoxins first enter the apical turn scala tympaniwhere they can disturb the neurophysiology of the apical ganglion cell dendrites.A low-frequency threshold elevation with decreased word recognition results.The sharp rise to a normal threshold for 1 or 2 kHz in MD reflects stimulationof adjacent basal portions of the basilar membrane by the envelope of activation

Gacek /Gacek 76

which spreads from the apex to base. With longevity of MD, the neurotoxiceffect on the spiral ganglion increases in a basal turn direction resulting in aneven frequency spectrum threshold elevation and poor word discrimination. A repeated neurotoxic effect on dendrites of spiral ganglion cells may lead to aretrograde degeneration of ganglion cells. This pathway for adverse effects onthe spiral ganglion is supported by histologic changes in the apical scala tympaniobserved in toxic labyrinthitis. End-stage MD is characterized by profoundlydecreased vestibular and auditory sensitivity with minimal balance symptomsand severe-to-profound sensorineural hearing loss.

Conclusion

A preponderance of immunologic, morphologic, radiologic and molecularevidence indicates that the clinical syndrome described by Prosper Ménière isthe result of a latent neurotropic viral vestibular ganglionitis which may be reactivated by a multitude of stressful stimuli to a host immune system unableto prevent recrudescence of the viral organism. MD differs from vestibular neuronitis, also a reactivated neurotropic viral vestibular ganglionitis, in that thevirus strain in MD follows a retrograde direction of flow to the perilymphaticcompartment where toxicity to cochlear neurons occurs.

References

1 Hallpike CS, Cairns H: Observations on the pathology of Ménière’s syndrome. J Laryngol Otol1938;53:625–655.

2 Yamakawa K: Über die pathologische Veränderung bei einem Ménière-Kranken. J OtorhinolaryngolSoc Jpn 1938;44:2310–2312.

3 Lindsay JR: Labyrinthine dropsy and Ménière’s disease. Arch Otolaryngol 1942;37:853–867.4 Kimura RS, Schuknecht HF: Membranous hydrops in the inner ear of the guinea pig after

obliteration of the endolymphatic sac. Pract Otorhinolaryngol 1965;27:343–354.5 Schuknecht HF: Pathology of the Ear. Cambridge, Harvard University Press, 1974.6 Kimura RS: Animal models of endolymphatic hydrops. Am J Otolaryngol 1982;3:447–451.7 Schuknecht HF, Northrop C, Igarashi M: Cochlear pathology after destruction of the endolymphatic

sac in the cat. Acta Otolaryngol (Stockh) 1968;65:479–487.8 Swart JG, Schuknecht HF: Long-term effects of destruction of the endolymphatic sac in a primate

species. Laryngoscope 1988;98:1183–1189.9 Tasaki I, Fernandez C: Modification of cochlear microphonics and action potentials by direct

currents. J Neurophysiol 1952;15:497–512.10 Schuknecht HF, Igarashi M: Pathophysiology of Ménière’s disease; in Pfaltz CR (ed): Controversial

Aspects of Ménière’s Disease. New York, Thieme, 1986, pp 46–54.11 Schuknecht HF, Richter E: Apical lesions of the cochlea in idiopathic endolymphatic hydrops and

other disorders: Pathophysiological implications. ORL J Otorhinolaryngol Relat Spec 1980;42:46–76.12 Schuknecht HF: Pathology of the Ear, ed 2. Philadelphia, Lea & Febiger, 1993, pp 235–244.13 Schuknecht HF: Delayed endolymphatic hydrops. Ann Otol Rhinol Laryngol 1978;87:743–748.


14 Schuknecht HF, Suzuka Y, Zimmerman C: Delayed endolymphatic hydrops and its relationship toMénière’s disease. Ann Otol Rhinol Laryngol 1990;99:843–853.

15 Ruckenstein MJ: Immunologic aspects of Ménière’s disease. Am J Otolaryngol 1999;20:161–165.

16 Bergstrom T, Edstrom S, Tjellstrom A, et al: Ménière’s disease and antibody reactivity to herpessimplex virus type I polypeptides. Am J Otol 1992;13:295–300.

17 Williams LL, Lowery HW, Shannon BT: Evidence of persistent viral infection in Ménière’s disease. Arch Otolaryngol Head Neck Surg 1987;113:397–400.

18 Calenoff E, Zhao J, Derlacki EL, et al: Patients with Ménière’s disease possess IgE reacting withherpes family viruses. Arch Otolaryngol Head Neck Surg 1995;121:861–864.

19 Arnold W, Niedermeyer HP: Herpes simplex virus antibodies in the perilymph of patients withMénière’s disease. Arch Otolaryngol Head Neck Surg 1997;123:53–56.

20 Furuta Y, Takasu T, Fukuda S, et al: Latent herpes simplex virus type I in human vestibular ganglia. Acta Otolaryngol Suppl (Stockh) 1993;503:85–89.

21 Ikeda M, Sando I: Endolymphatic duct and sac in patients with Ménière’s disease: A temporal bone histopathological study. Ann Otol Rhinol Laryngol Suppl 1984;93:540–546.

22 Adour KK, Hilsinger R, Byl FM: Herpes simplex polyganglionitis. Otolaryngol Head Neck Surg1980;88:270–274.

23 Adour KK, Byle FM, Hilsinger R: Ménière’s disease as a form of cranial polyneuritis. Laryngoscope1980;90:392–398.

24 Palva T, Horling L, Ylikoski J, et al: Viral culture and electron microscopy of ganglion cells inMénière’s disease. Acta Otolaryngol 1979;86:269–275.

25 Welling DB, Miles BA, Western L, Prior T: Detection of viral DNA in vestibular ganglion tissuefrom patients with Ménière’s disease. Am J Otol 1997;18:734–737.

26 Pitovski DZ, Robinson AM, Garcia-Ibanez E, Wiet R: Presence of HSV-1 gene products characteristic of active infection in the vestibular ganglia of patients diagnosed with acute Ménière’sdisease (abstract 457). 22nd Annu Midwinter Res Meet Assoc Res Otolaryngol St Petersburg Beach,February 1999.

27 Rosenstein, Pitovski D: Detection of herpes simplex virus type I latency associated DNA in humanvestibular ganglion by in situ polymerase chain reaction (abstract 261). 21st Meet Assoc ResOtolaryngol, St Petersburg Beach, February 1998.

28 Gacek RR: The pathology of facial and vestibular neuronitis. Am J Otolaryngol 1999;20:202–210.29 Ona A: The mammalian vestibular ganglion cells and the myelin sheath surrounding them. Acta

Otolaryngol Suppl (Stockh) 1993;503:143–149.30 Denny-Brown D, Adams RD, Fitzgerald PJ: Pathologic features of herpes zoster: A note on

geniculate herpes. Arch Neural Psychiatry 1949;51:216–231.31 Spoendlin H, Balle V, Bock G, Bredberg G, Danckwardt-Lillieström N, Felix H, Gleeson M,

Johnsson LG, Luciano L, Rask-Andersen H, Reale E, Reiss G, Schrott-Fischer A, Iurato S: Multi-centre evaluation of the temporal bones obtained from a patient with suspected Ménière’s disease.Acta Otolaryngol Suppl (Stockh) 1992;499:1–21.

32 Tsuji K, Velázques-Vallasenor L, Rauch S, Glynn R, Wall C III, Merchant S: Ménière’s disease:Temporal bone studies of the human peripheral vestibular system. Ann Otol Rhinol Laryngol2000;109 (Suppl 181):26–31.

33 Baringer JR, Swoveland P: Recovery of herpes simplex virus from human trigeminal ganglions. N Engl J Med 1973;288:648–650.

34 Meier JL, Straus SE: Comparative biology of latent varicella zoster virus and herpes simplex virusinfections. J Infect Dis 1992; 166(Suppl 1):S13–S23.

35 Cook ML, Stevens JG: Pathogenesis of herpetic neuritis and ganglionitis in mice: Evidence forintra-axonal transport of infection. Infect Immun 1973;7:272–288.

36 Galic M, Helms J: Elektronenmikroskopische Befunde am Bindegewebe von Nervus und Ganglionvestibuli bei Morbus Ménière. Arch Otorhinolaryngol 1982;236:67–79.

37 Kuypers HG, Ugolini G: Viruses as transneuronal tracers. Trends Neurosci 1990;13:71–75.38 Card JP: Exploring brain circuitry with neurotropic viruses: New horizons in neuroanatomy.

Anat Rec (New Anat) 1998;253:176–185.

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39 LaVail JH, Topp KS, Giblin PA, Garner JA: Factors that contribute to the transneural spread of herpes simplex virus. J Neurosci Res 1997;49:485–496.

40 Zemanick MC, Strick PL, Dix RD: Direction of transneural transport of herpes simplex virus I inthe primate motor system is strain-dependent. Proc Natl Acad Sci USA 1991;88:8048–8051.

41 Gacek R, Gacek M: The three faces of vestibular ganglionitis. Ann Otol Rhinol Laryngol, in press.42 Proctor LR: Results of serial vestibular testing in unilateral Ménière’s disease. Am J Otol 2000;

21:552–558.43 Wittmaack K: Die entzündlichen Erkrankungsprozesse des Gehörorganes; in Wittmaack K (ed):

Handbuch der speziellen pathologischen Anatomie und Histologie. Berlin, Springer, 1926, vol 2,pp 102–379.



The Pathology of Benign ParoxysmalPositional Vertigo


Our knowledge of the pathology in benign paroxysmal positional vertigo(BPV) has increased greatly since the clinical syndrome was first describedmore than 70 years ago by Bárány [1]. BPV represents the most commonvestibular disturbance seen in otology. Many clinical and histopathologicalobservations acquired over the past 35 years indicate that the sense organ usuallyresponsible for the position-provoked vertigo and vestibulo-ocular response isthe posterior canal crista of the undermost ear in the Hallpike positioning test[2–4]. Much less commonly, the lateral canal crista may be the responsiblesense organ based on the observation of a horizontal fatigable nystagmus in theprovocative position. Together with the description of highly specific gravitydeposits within the posterior canal or its cupula, these observations have led tothe development of nonsurgical (repositioning) [5–8] and surgical (singularneurectomy, posterior canal occlusion) [9–11] procedures to relieve the symptomsof BPV with preservation of hearing.

Based on the observations that basophilic deposits, presumably degener-ated otoconia, representing gravity-sensitive particles in the posterior canalampulla, are present either attached to or near the cupula of the posterior canal[2, 10, 12, 13], it was hypothesized that the highly specific gravity otoconiatransform the posterior canal crista into a gravity-sensitive sense organ. It hasbeen assumed that these otoconia are dislodged from the utricular macula byeither concussive or ischemic forces acting on the superior vestibular divisionsense organs [2, 12]. It has also been suggested that the otoconial debris may beeither embedded in the cupula (cupulolithiasis) or remain in a suspended statewithin the endolymph fluid compartment (canalolithiasis) [10]. These twoarrangements of dislodged otoconial debris are thought to be responsible for thepersistent and the intermittent clinical presentations of BPV.

However, some clinical features of BPV are not sufficiently explained bythe concept of cupulolithiasis or canalolithiasis [2]. These are: the limited

Chapter 6

The Pathology of Benign Paroxysmal Positional Vertigo 81

duration of the attack in spite of a maintained provocative head position, the fatigability of the vestibulo-ocular response on repeated testing and the pro-longed remissions of BPV in some patients. Furthermore, the onset of BPV following very different forms of injury is difficult to explain purely on amechanical basis. Most commonly, the preceding historical event prior to theonset of BPV is a vestibular disturbance suggestive of acute vestibular neuronitis.However, head injury, aging and various types of general surgery on other partsof the body under general anesthesia are well known as events that may precedethe onset of BPV.

A neural component in BPV had been suggested by Citron and Hallpike [4]and Lindsay and Hemenway [14], on the basis of degeneration in the superiorvestibular nerve of the temporal bone (TB) from patients whose onset of BPVwas idiopathic rather than traumatic. However, superior vestibular nerve degen-eration was considered an unusual finding in BPV because most patients withBPV demonstrate a normal vestibular response to caloric stimulation. Theseobservations were used to support the contention that with its nerve supplyintact the posterior canal crista is responsible for vertigo and the rotatoryvestibulo-ocular response following the provocative test.

Morphologic evidence of a neural component in BPV was described in theform of inferior vestibular ganglion degeneration and inflammation with a normalsuperior vestibular ganglion in the TB of 3 patients with the clinical findings ofBPV [15]. Furthermore, the cupulae of the posterior canal crista in all 3 TB did not contain basophilic material resembling otoconial debris. Basophilic particles were not identified within the lumen of the posterior semicircularcanal or its ampulla either. These findings suggest that the pathophysiology in BPV consists of a mechanical and a neural component. The mechanical com-ponent is the transformation of the posterior canal crista into a gravity-sensitivereceptor while the neural component consists of a change in the physiology ofinferior vestibular ganglion cells caused by viral inflammation. In this report, 2additional TB specimens from patients with chronic BPV were examined forpathologic changes in the posterior canal crista, the vestibular ganglion andmeatal ganglia of the facial nerve.

Material and Methods

Additional TB

TB were removed from 2 patients with clinical findings of BPV, placed in formalin fixative and decalcified. The TB were then embedded in celloidin, sections cut at 20 �m and stained with hematoxylin and eosin. Every tenth section was mounted and examinedunder the light microscope.

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Previously Examined TB

TB of the affected ear (downmost ear in the Hallpike test) from 3 previously reportedpatients with BPV were reviewed. Morphologic changes in the seventh and eighth cranialnerves were estimated by the techniques described in chapter 4 and listed in table 3(Appendix). Deposits in the labyrinthine sense organs and degeneration of the vestibulo-cochlear anastomosis and tympanic nerve were also described. These TB were horizontallysectioned and stained with hematoxylin and eosin.

Results

Additional TB

One TB is illustrated in detail since both TB show similar findings.

Case 1: TB Removed 5.5 h after DeathClinical History. This 48-year-old female was admitted to the hospital

at the age of 43 years for treatment of porphyria which was successful. Laterthat same year, she experienced sudden hearing loss in her left ear and vertigo.A hearing test revealed profound sensorineural hearing loss in the left ear andnormal hearing in the right. Caloric testing revealed a normal response in theright and a decreased response in the left ear. She was treated with vestibularsuppressants and multivitamins with the vertigo resolving after several days.The patient subsequently complained of brief vertigo on turning over in bed.Positional testing revealed a rotatory nystagmus lasting 15 s when the head wasturned to the left. There was no nystagmus when the head was turned to theright. The patient died from a myocardial infarction.

Histopathology of the Left TB. The organ of Corti was atrophic and totallyabsent in the basal 17 mm of the cochlea. It was flattened in the 17- to 23-mmarea of the cochlea and possessed a few scattered hair cells in the 23- to 32-mmregion. The ganglion cell loss averaged 30% throughout the cochlea with agreater loss in the basal turn. There were several concretions in the stria vascu-laris of the upper basal turn.

The geniculate ganglion of the facial nerve contained the normal numberof satellite cells (SC) around intact ganglion cells. No degenerated ganglioncells were found in the geniculate ganglion. Almost 50% of the ganglion cells inthe meatal ganglion were degenerated with an onion bulb form of collagenreplacement (fig. 1). Vestibular sense organs were normal and the superior divi-sion ganglion cells were each surrounded by 1–2 SC (fig. 2). Ganglion cellssupplying the saccular macula and the posterior canal crista were surrounded byan increased number of SC (more than 4 per ganglion cell). There were several


Fig. 1. a The meatal ganglion (MG) and facial nerve (F) are pulled away from thevestibular nerve and ganglion (VG). A few meatal ganglion cells (arrow) are left attached tothe vestibular nerve trunk. Degenerated ganglion cells (arrowhead) are present in the meatalganglion. b A higher-power view shows the circular deposition of collagen in degeneratedganglion cells (arrowheads) of the meatal ganglion.

Fig. 2. The superior vestibular ganglion contained a normal number (1–2) of SC perganglion cell.

Gacek /Gacek 84

Fig. 3. Several fascicles of degenerated axons (arrows) were present in the inferiorvestibular nerve trunk.

small blue-stained plaques in the inferior vestibular ganglion and several fasci-cles of degenerated axons in the inferior vestibular nerve trunk (fig. 3). The posterior canal crista was also capped by a shrunken cupula with a smallbasophilic deposit (fig. 4).

Previously Examined TB

Three previously reported TB (table 3, see Appendix) contained degener-ated ganglion cells in the meatal ganglion of the seventh cranial nerve and focalaxonal degeneration in the inferior vestibular nerve [15]. The superior divisionvestibular nerve and ganglion were normal in all 3 TB. Degeneration in the spiral ganglion was present in the basal turn and consistent with an age-relateddecrease. The vestibulocochlear anastomosis was partially degenerated in all 3 TB, and the tympanic nerve was degenerated in 1 but normal in 2 TB.Concretions were found in vestibular sense organs of 2 and the organ of Corti of

1 TB. No concretions were observed in 1 TB. The concretions will be discussedin chapter 8.

Discussion

The observations in the 2 current TB and 3 previously reported TB supporta role for an inflamed inferior vestibular ganglion in the pathogenesis of BPV. Morphologic changes consisted of focal axonal degeneration in the infe-rior vestibular nerve trunk and/or an increased number of SC and inflammatorycells around ganglion cells of the inferior division which supply the saccularmacula and the posterior semicircular canal crista. Focal axonal degeneration in the inferior vestibular nerve trunk reflects loss of ganglion cell clustersdegenerated because of past viral infection, while the increase in the supportingand inflammatory cells around the ganglion cells represents a response to inflam-matory changes in the ganglion [16]. The acute inflammatory process in ganglioncells may be responsible for active periods of BPV. The exact pathoneurophysiol-ogy is not known, but it may represent a change in the ionic gradient across the ganglion cell membrane caused by repeated viral passage through the mem-brane with exacerbation of latent virus. Membrane defects in the cell wall could be responsible for loss of the ionic gradient making the cell hyper-excitable in response to a mechanical stimulus at the end organ. Sufficientlysevere or repeated exacerbations of virus recrudescence would be capable of celldestruction, leading to axonal degeneration [17]. The limited duration of thevestibulo-ocular response in the maintained provocative position as well as


Fig. 4. The cupula of the posteriorcanal crista contained a small basophilicdeposit (arrow).

the fatigability of the response to repeat testing are characteristics that could be explained by a ganglion cell that is unable to maintain a sustained res-ponse. Therefore, the presence and reappearance of BPV intermittently overlong periods of time may be caused by virus recrudescence and return to a latentstate [18].

A mechanical component remains a part of this concept, not only becauseof the reported basophilic deposits in the posterior canal cupula in TB of BPVpatients, but also because the mechanical stimulus is provided by the head-positioning maneuver. Basophilic deposits were not seen in the posterior canalcupula of the 3 previously reported patients with inferior vestibular ganglionitis.However, a small deposit was found in the posterior canal cupula of the TB reported. The argument can be made that in some of these cases the depositswere free floating in the membranous limb of the posterior canal. This conten-tion cannot be answered with confidence based on the available material.

In all 5 TB, the superior vestibular division ganglion was normal; therewere no degenerated ganglion cells, and a normal low density of SC surroundedthe ganglion cells. Evidence of past and current inflammatory changes wasfound in the inferior vestibular ganglion and/or the inferior vestibular nervetrunk. These changes consisted of an increased number of SC and/or inflamma-tory cells around ganglion cells in the inferior vestibular ganglion or focalaxonal degeneration in the proximal nerve trunk of 1 TB. The inflammatorynature of the change in the vestibular ganglion is supported by a decreasedcaloric response initially in the affected ear of case 1 following the initialepisode of vertigo which had recovered by the time of TB removal years laterwhen the superior vestibular ganglion was found to be normal. Such a reversalin vestibular sensitivity can be explained by an inflammatory lesion.

The role of reactivated neurotropic virus in the ganglion is supported by thedivergent events that precede the onset of vestibular neuronitis [19] or BPV[20–22]. These are: head trauma, association with an inflammatory process inthe upper aerodigestive tract (sinusitis), the stress of recovering from a majorsurgical procedure with general anesthesia as well as a decreased host responsedue to a senescent immune system. Examples of stressors capable of reacti-vating virus are: upper respiratory tract infection, ultraviolet light, trauma, surgery, emotional upset, headache, dental infection and pregnancy. Until nowit has been difficult to causally relate the onset of BPV following surgery undergeneral anesthesia. Since the use of singular neurectomy [23] in patients disabled by BPV, we have encountered 16 patients with chronic disabling BPV of the posterior canal following surgery on other areas of the body [21].These have included frontal sinus surgery, back surgery, gynecological surgery,heart surgery and abdominal surgery. The peak incidence of BPV in the adultyears (�50 years) is typical of reactivation of latent virus.

Gacek /Gacek 86

Numerous authors have observed the co-occurrence of BPV in the ear withvestibular neuronitis [19] or Ménière’s disease [22]. Proctor [22] reported that44% of the 122 patients with Ménière’s disease whom he followed for severalyears experienced BPV in the involved ear. The report of Lindsay and Hemenway[14] of BPV in a patient with degeneration of the superior vestibular ganglionwas one of the early descriptions of co-occurrence of vestibular neuronitis andBPV. The concept of various forms of recurrent vestibulopathy caused byvestibular ganglionitis provides a logical basis for the coexistence of differentvestibular syndromes in the same ear.

References

1 Bárány R: Diagnose von Krankheitserscheinungen im Bereiche des Otolithenapparates. ActaOtolaryngol (Stockh) 1921;2:434–437.

2 Schuknecht HF, Ruby RR: Cupulolithiasis. Adv Otorhinolaryngol 1973;20:434–443.3 Gacek RR: Transection of the posterior ampullary nerve for the relief of benign paroxysmal

positional vertigo. Ann Otol Rhinol Laryngol 1974;83:596–605.4 Citron L, Hallpike CS: Observations upon the mechanism of positional nystagmus of the so-called

‘benign paroxysmal type’. J Laryngol 1956;70:253–259.5 Brandt T, Daroff RB: Physical therapy for benign paroxysmal positional vertigo. Arch Otolaryngol

1980;106:484–485.6 Semont A, Freyss G, Vitte E: Curing BPPV with a liberatory maneuver. Adv Otorhinolaryngol

1988;42:290–293.7 Epley JM: The canalith repositioning procedure: For treatment of benign paroxysmal positional

vertigo. Otolaryngol Head Neck Surg 1992;107:399–404.8 Epley JM: Particle repositioning for benign paroxysmal positional vertigo. Otolaryngol Clin

North Am 1996;29:323–331.9 Gacek RR: Technique and results of singular neurectomy for the management of benign paroxys-

mal positional vertigo. Acta Otolaryngol (Stockh) 1995;115:154–157.10 Parnes LS, McClure JA: Posterior semicircular canal occlusion for intractable benign paroxysmal

positional vertigo. Ann Otol Rhinol Laryngol 1990;99:330–334.11 Parnes LS: Update on posterior canal occlusion for benign paroxysmal positional vertigo.

Otolaryngol Clin North Am 1996;29:333–342.12 Hall SF, Ruby RR, McClure JA: The mechanics of benign paroxysmal vertigo. J Otolaryngol

1979;8:151–158.13 Moriarty B, Rutka J, Hawke M: The incidence and distribution of cupular deposits in the labyrinth.

Laryngoscope 1992;102:56–59.14 Lindsay JR, Hemenway WG: Postural vertigo due to unilateral sudden partial loss of vestibular

function. Ann Otol Rhinol Laryngol 1956;65:692–708.15 Gacek R, Gacek M: Update on the pathology and management of benign paroxysmal positional

vertigo. Otorhinolaryngol Nova 1998;8:235–244.16 Cook ML, Stevens JG: Pathogenesis of herpetic neuronitis and ganglionitis in mice: Evidence for

intra-axonal transport of infection. Infect Immun 1973;7:272–288.17 Gacek RR: The pathology of facial and vestibular neuronitis. Am J Otolaryngol 1999;20:

202–210.18 Meier JL, Straus SE: Comparative biology of latent varicella-zoster virus and herpes simplex virus

infections. J Infect Dis 1992;166(suppl 1):S13–S23.19 Schuknecht HF, Kitamura K: Vestibular neuronitis. Ann Otol Rhinol Laryngol Suppl 1981;

90:1–19.


20 Katsarkas A, Outerbridge JS: Nystagmus of paroxysmal positional vertigo. Ann Otol RhinolLaryngol 1983;92:146–150.

21 Gacek RR: Singular neurectomy update II: Review of 102 cases. Laryngoscope 1991;101:855–862.

22 Proctor LR: Results of serial testing in unilateral Ménière’s disease. Am J Otol 2000;21:552–558.23 Gacek RR: Singular neurectomy update. Ann Otol Rhinol Laryngol 1982;91:469–473.

Gacek /Gacek 88


A Classification of Recurrent Vestibulopathy


Intermittent vertigo represents one of the most disabling symptomsencountered in otologic practice. The recurrent nature of this disability impliesa reversible alteration in vestibular nerve physiology caused by changes in the neuron or its environment. Three of the most common clinical syndromes manifesting as recurrent vertigo are benign paroxysmal positional vertigo(BPV), Ménière’s disease (MD) and vestibular neuronitis (VN). The morphologicevidence presented in previous chapters supported by molecular [1, 2],immunologic [3–6] and clinical observations [7–19] indicates that these com-mon, and some less common, recurrent vestibulopathies are manifestations ofreactivation of latent viral vestibular ganglionitis.

The agents responsible for the ganglionitis are neurotropic (NT) viruses,likely herpes simplex (HSV) or zoster virus. Other NT viruses that may beincluded in this group are cytomegalovirus, Epstein-Barr and pseudorabiesvirus. The ubiquity of HSV accounts for the high exposure rates recorded in theworld population. Elevated serum antibody titers to HSV-1 have been recordedin 70% of 25-year-olds, while at the age of 60 years the rate is over 90% [20].After the NT virus has entered a sensory nerve, it may acquire a latent state inits ganglion cells. Reactivation of the virus from latency is reflected in clinicalsigns and symptoms.

Because the clinical syndromes with recurrent vertigo are varied, it is usefulto construct a classification system based on vestibular ganglionitis [21]. We pro-pose a new classification system based on three bodies of information: (1) areview of temporal bone (TB) specimens, (2) case reports and (3) a clinical series.

Review of TB Specimens

A review of 20 TB with VN, 10 TB with MD and 3 with BPV is summa-rized in tables 1, 2 and 3 in the Appendix. The similarity of morphologic

Chapter 7

changes in the facial nerve meatal ganglion (MG) and vestibular nerves supports a common etiology. The vestibular nerve and ganglion (VG) pathologywas limited to the inferior vestibular division in all cases of BPV and in bothsuperior and inferior divisions in VN and MD. These changes were not found in TB from patients with similar age, sex and sense organ disorders but withouta vestibular disorder (table 4, see Appendix).

Case Reports

TB case reports illustrate the location of VG pathology in VN, MD and BPV.

Vestibular Neuronitis

A 71-year-old male with a 5-year history of prostatic cancer with orbitaland brain metastases was admitted to the hospital for severe vertigo and nausea.A hearing test showed a bilateral high-frequency sensorineural hearing loss withdiscrimination scores of 88% (right) and 68% (left). There was a spontaneousnystagmus to the right and a diminished caloric response on the left. He died 19days later from brainstem and cerebellar infarction.

Histopathology (Left TB)The geniculate ganglion did not have degenerated neurons, but the ganglion

cells were surrounded by an abundant number of satellite cells (SC). In the MG,there were several scattered degenerated ganglion cells replaced by collagen-likematerial (fig. 1a, b). Intact ganglion cells were surrounded by many SC. Thecristae and maculae appeared to contain a normal number of hair cells and sup-porting cells. Several fascicles of axonal degeneration were observed in the supe-rior vestibular nerve trunk (fig. 2). Smaller fascicles of degenerated nerve fiberspassed between neurons surrounded by many SC and inflammatory cells in theVG. Consistent with normal hearing thresholds and word discrimination for hisage of 71 years, the organ of Corti was shrunken, but the pillar cells separated anormal number of internal and external hair cells. The organ of Corti was missingin the lower basal turn. The spiral ganglion cells appeared reduced in numberexcept for the extreme basal end of the cochlea where they were absent.

Benign Paroxysmal Positional Vertigo

A 65-year-old male alcoholic suffered head injury with several hours ofunconsciousness. Six months later, he was diagnosed as having posttraumatic

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A Classification of Recurrent Vestibulopathy 91

Fig. 1. a Photomicrograph of the MG in a case of VN (case 9, tab. 1). Arrowheads indi-cate degenerated ganglion cells replaced by a collagen-like material. F � Facial nerve. b Ahigher-power view of the degenerated ganglion cells in a illustrates the laminated pattern of collagen deposition (arrowheads).

Fig. 2. The vestibular nerve in the case of VN contained many fascicles of degen-erated axons (arrows).

normotensive hydrocephalus. During admission to the hospital, he complained ofrecurrent vertigo for several months. The vertigo lasted a few minutes and wasassociated with nausea and vomiting. There was a mild spontaneous nystagmusto the left and a tendency to fall to the left. Positional (Hallpike) tests revealed –in the position with the left ear down – a rotatory clockwise nystagmus with abrief latency, a short duration and fatigability on repeat testing. When the rightear was placed down, no nystagmus was observed. Bithermal caloric stimulationwas normal and symmetric. A hearing test revealed a high-frequency sensorineuralhearing loss on the left. Speech discrimination was normal in both ears.

Histopathology (Left TB)The tympanic membrane, ossicles and mastoid air cell system were nor-

mal. No evidence of TB fracture was present. There was a loss of hair cells inthe basal turn of the cochlea (basal 6 mm) and atrophy of the stria vascularis inthe upper turns of the cochlea. The spiral ganglion had a slight loss of neuronsin the basal turn. The cupula of the posterior canal crista was reasonably formedbut shrunken and contained a few small basophilic deposits (fig. 3). The facialnerve MG contained a heavy infiltration of satellite cells, which surroundedintact and degenerated ganglion cells (fig. 4). The ganglion of the superiorvestibular division contained intact ganglion cells surrounded by a normal

Gacek/Gacek 92

Fig. 3. In the case of BPV (case 2, tab. 3), the posterior canal crista revealed roundbasophilic deposits (arrow) in the cupula. These are artifacts, not degenerated otoconia.

density of SC (fig. 5a). No degenerated axons were detected in the superiorvestibular nerve trunk. The inferior VG was comprised of ganglion cells sur-rounded by an increased number of SC and inflammatory cells (fig. 5b). Severalfascicles of degenerated axons in the inferior nerve trunk could be tracedthrough the ganglion toward the singular nerve (fig. 6).

Ménière’s Disease

A 76-year-old female had had a fluctuant but slowly progressive hearingloss for many years. An audiogram at the age of 72 years revealed a bilateralsevere sensorineural hearing loss with flat audiometric patterns at 70 dB on theright and 90 dB on the left. Speech discrimination scores were 28% in the rightear and 0 in the left. At the age of 73 years, she began to experience suddenepisodes of vertigo with falling occasionally. At the age of 76 years, she died ofcerebral hemorrhage and pontine infarction.

Histopathology (Right TB)There was severe endolymphatic hydrops of the cochlear and vestibular

labyrinth. Reissner’s membrane was displaced to make contact with the walls ofthe scala vestibuli. There was atrophy of the stria vascularis in a patchy pattern


Fig. 4. The MG in a BPV case contained several degenerated (arrowheads) and intactganglion cells surrounded by many SC (open arrows). F � Facial nerve.

Gacek/Gacek 94

throughout the middle and apical turns. There was a scattered loss of hair cellsin the organ of Corti. The spiral ganglion was markedly reduced to 25% of normal. The saccule was distended, and the saccular wall was attached to thestapes footplate by a layer of fibrous tissue (fig. 7). There were outpouchings inthe walls of the utricle and all three ampullae. The geniculate ganglion did not have any degenerated ganglion cells and a normal density of SC. The MG contained intact and degenerated neurons surrounded by an abundance of SC(fig. 8). Superior and inferior VG cells were surrounded by many SC. Fasciclesof degenerated axons were seen in the vestibular nerve trunk (fig. 9).

Clinical Series

Forty-five consecutive patients evaluated for recurrent vertigo during a 14-week period demonstrated coexistence of multiple cranial neuropathies with

Fig. 5. a The superior vestibular division ganglion cells were surrounded by a normal number of SC. b The inferior vestibular division ganglion cells were surrounded by aheavy infiltrate of SC and inflammatory cells. A fascicle of degenerated nerve fibers (*) isseen passing through the ganglion.


Fig. 6. There were fascicles of degenerated axons (arrow) in the vestibular nerve trunk.

Fig. 7. A distended saccular wall was attached to the stapedial footplate (FP) by fibroustissue (arrow) in MD TB. S � Saccular macula.

same-sidedness (table 1). There were 29 female and 16 male patients rangingfrom 31 to 93 years in age (mean � 62 years). Thirteen patients had a diagnosisof MD and BPV in the same ear; 4 of these patients also gave a history of herpes labialis or herpes zoster on the side of the affected ear. Fourteen patientsmanifested VN and BPV in the same ear; 3 gave a history of herpes labialis onthe side of the affected ear. All 9 patients with BPV alone gave a history of herpes labialis or herpes facialis on the side provoking vertigo. Five patientswith a history of idiopathic facial paralysis developed VN (n � 2), BPV (n � 2)or MD (n � 1) in the same ear. One of these experienced sequential idiopathicfacial paralysis and VN bilaterally. The 4 remaining patients in the series presented a single vestibulopathy (MD � 2, BPV � 2) without an associatedcranial neuropathy. The onset of vestibular symptoms in 2 of these patients followed surgery on the eye (n � 1) and sinus infection (n � 1).

MRI was performed on 2 patients in this clinical series. Patient A.P. is a 52-year-old female with a 2-year history of right aural fullness, fluctuating hear-ing loss and recurrent vertigo (from 15 min to 1 h in duration). The right ear hada low-frequency sensorineural hearing loss (40 dB) and 88% word discrimination

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Fig. 8. There were degenerated (arrows) and intact ganglion cells in the MG of thefacial nerve (F) in MD.

with normal hearing in the left ear. ENG demonstrated a 70% right canal paresis.MRI with contrast revealed focal enhancement in the distal internal auditorycanal (fig. 10). A middle cranial fossa approach was used to excise the vestibularnerve and VG. Pathology reported neural tissue with ganglion cells surroundedby many small dark cells and focal axonal fibrosis (fig. 11). Immunoperoxidasestaining with antibodies to HSV was positive in ganglion cells.


Fig. 9. Several fascicles of degenerated nerve fibers (open arrows) were present in thevestibular nerve trunk.

Table 1. Polyneuropathy in patients with vertigo (n � 45)

Vestibular nerve Facial nerve Trigeminal nerve n

MD � BPV 0 4 13VN � BPV 0 3 14BPV 0 9 9VN (2), BPV (2), MD (1) 5 0 5MD 0 0 2BPV 0 0 2

IFP � Idiopathic facial paralysis; n � number.

Patient K.M. is a 45-year-old male with an 8-month history of recurrentvertigo (several hours duration) without hearing loss and positional vertigo(20–25 s) with the right ear down. ENG demonstrated a 32% right canal paresisand a positive right Hallpike positional test. Hearing was normal. An enhanced

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Fig. 10. Enhanced MRI of a 52-year-old female with a history of right MD and 70%right canal paresis showed focal enhancement (arrow) in the internal auditory canal.

Fig. 11. The excised right vestibular ganglion revealed an increased number of SC and inflammatory cells surrounding ganglion cells (open arrows) and focal axonal degeneration (*).


Fig. 12. a Enhanced MRI of a 45-year-old male with a history of VN and BPV in theright ear. Focal enhancement is seen in the internal auditory canal (arrow). b The focalenhancement (arrow) is decreased 2 months later. Note the ‘tail’ of the enhanced area.

MRI revealed focal enhancement in the right internal auditory canal (fig. 12a).Repeat MRI 2 months later showed decreased enhancement in the right internalauditory canal (fig. 12b).

Discussion

Morphologic [21, 22], immunologic [3–6] and molecular [1, 2] evidencesupports a role for NT virus (herpes subfamily) vestibular ganglionitis as thecause of recurrent vertigo in VN, MD and BPV. Degeneration of ganglion cellsin the MG of the facial nerve with absence of degenerated neurons in the geniculate ganglion suggests a role of the MG in transmission of NT virus to the adjacent VG during the early introduction of virus [22]. In the 33 TB of VN, MD and BPV patients, only 2 MG did not contain degenerated ganglioncells, while all 33 vestibular nerves exhibited axonal degeneration. If the virus

assumes a latent state following initial infection of the neuron, it may be reacti-vated and replicated at some later time by unusual stress [23].

When the NT virus is reactivated, it travels by axoplasmic transport alongthe neuron’s appendages. If the transport is in an anterograde direction, the virusis carried toward the central nervous system, while retrograde transport willcarry the virus in the peripheral nerve branches to the sense organ [24–27]. Thedirection of intra-axonal flow is dependent on the virus strain, especially withHSV. The H 129 strain of HSV-1 is carried preferentially in an anterogradedirection, while the McIntyre B strain follows a retrograde direction of flow tothe periphery. This directionality of flow determines to a large degree the clinicalexpression of NT viral ganglionitis.

The mechanism by which vestibular neuronal activity is altered to producevertigo is not known. However, virus activation and release into the extracellu-lar space disrupts the ganglion cell wall with leakage of ionic levels on eitherside of the cell wall [28]. Since neuronal excitability is dependent on the ionicgradient across the cell membrane, loss of this gradient by flow of K� to theouter coat of the membrane where it displaces bound Ca2� may be part of theexplanation. Recurrent disruption of the ganglion cell membrane may even-tually cause neuronal death. The whorl-like replacement of the neuronal cytoplasm by SC may be an attempt to repair the plasma membrane disrupted byvirus release.

The SC has long been felt to be intimately related to its ganglion cell [29, 30]. SC may support the neuron metabolically during prolonged activity. This suggestion is supported by a decreased nucleic acid content in SC while neuronal nucleic acid is increased in the superior cervical ganglion following prolonged (3-hour) stimulation [29]. Furthermore, SC proliferate in response toincreased metabolic or synaptic activity. The role of SC in the NT viral infec-tion of a ganglion may represent a response to increased neural activity as wellas the need to limit the spread of virion release from ganglion cells. Spread ofvirus to adjacent ganglion cells may be carried over SC which proliferate as theyenvelope virus protein. Therefore, it is common for groups of ganglion cells to be involved in the inflammatory process.

Degeneration of clusters of ganglion cells in the superior vestibular divi-sion was reflected in focal axonal degeneration of the nerve trunk in TB of VNand MD. The inferior VG was also involved in the inflammatory process insome TB with these two vestibulopathies. However, degeneration was restrictedto the inferior vestibular nerve in TB with BPV.

The coexistence of more than one vestibular syndrome in the same ear hasfrequently been observed in clinical practice [17]. Proctor [31] reported thatalmost half of 122 patients with unilateral MD demonstrated BPV in the sameear. The co-occurrence of BPV and VN in the same ear was noted by Lindsay

Gacek/Gacek 100

and Hemenway [32] and Schuknecht and Kitamura [17]. The coexistence ofmultiple vestibulopathies in the same labyrinth is not explained by current concepts of MD and BPV. However, the morphologic evidence of inflamma-tory/degenerative changes in different regions of the VG for MD or VN andBPV offers a basis for multifocal vestibulopathy.

Idiopathic otalgia is a frequent associated symptom in patients with recurrent vertigo. Neuropathy of the glossopharyngeal (ninth cranial) nerve can be assumed to be caused by NT viral organisms. However, this assump-tion has not been supported by clinical or TB evidence. The clinical presenta-tion is that of recurrent pain deep in the ear canal. The tympanic branch of the ninth nerve is the likely neural structure responsible for such recurrent otalgia. Occasionally the act of swallowing initiates the pain syndrome. Theafferent neural pathways from the oropharynx, tonsils, base of tongue andepiglottis offer a portal of entry for NT viruses of the herpes family similar tothat into the seventh nerve system (chapter 2, fig. 20). The integrity of the tympanic nerve (Jacobson’s) was assessed in its location on the lateral surfaceof the promontory in the vestibulopathic and the control TB (tables 1–4,Appendix). The nerve in this location was judged to be normal or degenerated(fig. 13). The nerve was partially degenerated in 11 out of 33 vestibulopathic


Fig. 13. a A normal tympanic nerve with 2 ganglion cells (arrows) in the TB from a 61-year-old male with exostoses of the ear canal. b A partially degenerated (*) tympanicnerve in an 80-year-old female with BPV.

TB (33%) with a similar ratio for VN, MD and BPV. In 4 out of 20 control TB (20%), the tympanic nerve was partially degenerated. The segregation of degenerated fibers in the TN supports the notion that a functional component(sensory) is affected.

Conclusion

These observations support the view that the syndromes of VN, BPV andMD are clinical expressions of viral vestibular ganglionitis, probably from the�-herpes virinae family. Several factors may determine the ‘face’ presented inindividual patients. These are: (1) the amount of virus present (viral load); (2) the virus type and strain; (3) the location and number of affected VG cells,and (4) host resistance. It is possible that other clinical presentations of recur-rent vertigo are expressions of vestibular ganglionitis. Innovative clinical termshave been used to describe these presentations (i.e. atypical vestibular neuritis,recurrent vestibulopathy, idiopathic vestibulopathy and psychogenic vestibu-lopathy). The correlation of clinical and functional deficits with histopathologicchanges may be used to classify vestibular disorders caused by vestibular gan-glionitis. The portion of VG affected and the type of NT virus responsible aretwo major descriptors in such a classification (table 2).

Since the spread of NT virus typically occurs in clusters of ganglion cells[33], separate divisions or branches of the vestibular nerve may be affectedleading to end-organ-specific expressions of vertigo. When the superior or infe-rior divisions of the VG are affected, the clinical picture is vestibular neuronitisor BPV, respectively. The occurrence of both VN and BPV in the same earreflects infection of both VG divisions. It is possible that a small cluster ofinflamed ganglion cells representing neural input from a single sense organ (i.e. utricle) may produce a specific type of balance disturbance (Tumarkin’s

Gacek/Gacek 102

Table 2. Classification of recurrent (viral) vestibulopathies

Anterograde virus strain (hearing preserved)Superior vestibular ganglionitis (vestibular neuronitis, vestibular MD)Inferior vestibular ganglionitis (BPV)Superior and inferior vestibular ganglionitis (vestibular neuronitis and BPV)

Retrograde virus strain (hearing affected)Superior vestibular ganglionitis (MD, neurolabyrinthitis)Subtype: utricular ganglionitis (Tumarkin’s otolithic crisis)

Superior and inferior vestibular ganglionitis (MD and BPV)

otolithic crisis). The absence of auditory defects in two ‘faces’ would reflect an anterograde virus strain in the VG. On the other hand, the presence of a sensorineural hearing loss together with episodic vertigo (MD) is caused by aretrograde strain of virus, which is transported along vestibular nerve branchesand released into the perilymphatic compartment causing a toxic labyrinthitis.

References

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2 Arbusow V, Schulz P, Strupp M, Dieterich M, et al: Distribution of herpes simplex virus in type Iin human geniculate and vestibular ganglion: Implications for vestibular neuritis. Ann Neurol1999;46:416–419.

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4 Bergstrom T, Edstrom S, Tjellstrom A, et al: Ménière’s disease and antibody reactivity to herpessimplex virus type I polypeptides. Am J Otol 1992;13:295–300.

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6 Arnold W, Niedermeyer HP: Herpes simplex virus antibodies in the perilymph of patients withMénière’s disease. Arch Otolaryngol Head Neck Surg 1997;123:53–56.

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Laryngoscope 1980;90:392–398.9 Schuknecht HF, Igarashi M: Pathophysiology of Ménière’s disease; in Pfaltz CR (ed): Contro-

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613–620.13 Pedersen E: Epidemic vertigo: Clinical picture, epidemiology, and relation to encephalitis. Brain

1959;82:566–580.14 Coats A: Vestibular neuronitis. Acta Otolaryngol (Stockh) 1969;suppl 251:1–32.15 Dix M, Hallpike C: The pathology, symptomatology and diagnosis of certain common disorders

of the vestibular system. Ann Otol Rhinol Laryngol 1952;61:987–1016.16 Shimizu T, Sekitani T, Hirata T, Hara H: Serum viral antibody titer in vestibular neuronitis. Acta

Otolaryngol (Stockh) 1993;suppl 503:74–78.17 Schuknecht HF, Kitamura K: Vestibular neuritis. Ann Otol Rhinol Laryngol Suppl 1981;90:1–19.18 Nadol JB: Vestibular neuritis. Otolaryngol Head Neck Surg 1995;12:162–172.19 Fenton JE, Shirazi A, Turner J, Fagan P: Atypical vestibular neuritis: A case report. Otolaryngol

Head Neck Surg 1995;112:738–741.20 Smith IW, Peutherer JF, MacCallum OF: The incidence of herpes virus hominis antibody in the

population. J Hyg 1967;65:395–408.21 Gacek R, Gacek M: The three faces of vestibular ganglionitis. Ann Otol Rhinol Laryngol, in press.22 Gacek RR: The pathology of facial and vestibular neuronitis. Am J Otolaryngol 1999;20:

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24 Zemanick MC, Strick PL, Dix RD: Direction of trans-neural transport of herpes simplex virus I in the primate motor system is strain-dependent. Proc Natl Acad Sci USA 1991;88:8048–8051.

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function. Ann Otol Rhinol Laryngol 1956;65:692–708.

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Efferent System Degeneration inVestibular Ganglionitis

Richard R. Gacek

It has been customary for otologists to regard the function and dysfunctionof the inner ear in terms of the afferent pathway from the auditory and vestibularsense organs. Hearing and balance are major forms of the body’s interaction withthe environment. In the preceding chapters, the pathology in the vestibular system’sconduit to the brainstem has been described which accounts for recurrent disrup-tions in the physiology of balance. The neuron-specific nature of these degener-ative changes suggests recrudescent neurotropic virus injury in sensory ganglia.Degeneration of the auditory sense organ and/or ganglion may be on the samebasis as the vestibular nerve pathology or coexist because of age, noise exposure,ototoxic drug exposure and other unknown causes. The concept that recurrent dis-ruption of vestibular nerve physiology is caused by a neurotropic virus is supportedby an enlarging body of immunologic, morphologic and molecular evidence.

The efferent neural system has been largely ignored in the evaluation ofauditory and vestibular symptoms in patients with labyrinthine pathology.Dysfunction of efferent axons is likely in vestibular ganglionitis because of theirclose anatomical relationship in Scarpa’s ganglion. Efferent axons to the labyrinthemerge from the brainstem in the center of the vestibular nerve (chapter 2, fig. 12,13) where they diverge at the saccular portion of Scarpa’s ganglion. The cochlearefferents (olivocochlear bundle, OCB) leave in the vestibulocochlear anastomosis(VCA) to enter Rosenthal’s canal as the intraganglionic spiral bundle whenceefferent axons (myelinated and unmyelinated) are given off toward the habenulaperforata and the organ of Corti [1–5]. Vestibular efferents also diverge from theparent bundle within Scarpa’s ganglion (chapter 2, fig. 11, 13). In the superiorvestibular division, they first appear in fascicles and individual fibers whichgradually disperse and branch as they enter the vestibular nerve branches [4, 6].Efferent nerve fibers to the saccular and posterior ampullary nerves maintain adispersed pattern throughout their course toward the sense organs.

Chapter 8

This chapter presents morphologic evidence observed in the 53 temporalbones (TB) summarized in tables 1–4 in the Appendix which suggest a degener-ative effect on the efferent system by vestibular ganglionitis.


TB Specimens

The TB included in this report are those described in the chapters on vestibular neuronitis (VN), Ménière’s disease (MD) and benign paroxysmal positional vertigo (BPV).They consist of 33 TB (VN � 20, MD � 10, BPV � 3) that were formalin fixed, celloidinembedded, sectioned at 20 �m in a horizontal plane and stained with hematoxylin and eosin(tables 1–3, Appendix). Twenty TB without evidence of vestibular ganglion degeneration or ahistory of vertigo represent a control series of TB examined in the light microscope (table 4,Appendix).

Light Microscopy

Examination in a light microscope of all sections from each TB were made at both low(�40) and high (�100, �200) magnifications. In addition to morphologic changes in thelabyrinth and its nerve supply described in chapters 4–7, the following structures were examined.

(1) The integrity of the OCB was evaluated in the VCA at its takeoff from the inferiorvestibular (saccular) ganglion. The VCA was determined to be normal (fig. 1) or degenerated,based on the presence or absence of myelinated nerve fibers. Total degeneration of the bundle was based on the absence of myelinated nerve fibers and a presence of Schwann cellnuclei (fig. 2). More often, the VCA was partially degenerated (fig. 3) as compared to a normal VCA. Efferent vestibular axons do not travel in a bundle separated from afferentaxons and cannot be identified without special techniques (acetylcholinesterase localization).

(2) The sense organs and associated epithelial structures of the labyrinth were examinedfor degenerative changes. Deposits (concretions) in the labyrinth have been used to desig-nate degeneration in the past. The following criteria were used to establish the presence of a concretion:

(a) concretions were usually circular with slight irregularities (fig. 4); sometimes theyappeared flattened if there was end organ compression from the preparation process(fig. 5); they appeared dark or light blue with the hematoxylin component of thestain; the solid nature of the deposit prevented visualization of underlying cellularstructures; stain material deposited as artifact allows visualization of underlyingstructures (fig. 6);

(b) concretions were located between supporting and sensory cells of the neuro-epithelium;

(c) the deposits were usually found within the boundaries of the neurosensory epithe-lium but sometimes in a nerve branch supplying the sense organ; concretionslocated in the meninges of the internal auditory canal were not included in thisassessment.

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Efferent System Degeneration in Vestibular Ganglionitis 107

Fig. 1. A normal VCA is shown afterits takeoff from the saccular nerve (S) whichis partially degenerated (*). Case 3, table 1(Appendix).

Fig. 2. Completely degenerated VCAat its divergence from the saccular nerve (S).Case 12, table 1 (Appendix).

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Fig. 3. Partially degenerated VCAafter its emergence from the saccular nerve(S). Open arrow � concretion in internalauditory canal. Case 7, table 2 (Appendix).

Fig. 4. Three concretions (open arrows) are shown in the neuroepithelium of the posterior canal crista.

Concretions

The concretions listed in tables 1–4 (Appendix) were reconstructed on a cochleogramand a vestibulogram to illustrate the spatial arrangement of end organ concretions in the 53TB (33 experimental, 20 control).


Fig. 5. This deposit in the organ of Corti (open arrow) is somewhat flattened due tocompression artifact.

Fig. 6. Saccular macula with a concretion (open arrow) in a nerve approaching the neuroepithelium and a blue stain droplet (a) as artifact.

Results

Concretions were found in two groups of structures. Most were located inthe auditory and vestibular neurosensory epithelium and their nerve bundles.These morphologic changes have not been previously described. The secondgroup of deposits was found in areas associated with cochlear blood flow. Theseincluded the stria vascularis and the spiral prominence. Deposits or concretionsin these structures have been described by others [7–11].

The majority of concretions (deposits) appeared as spherical accumulationsof dense material which takes the nuclear (hematoxylin) stain in the techniqueused for routine human TB histopathology. Most of the deposits were foundwithin the neuroepithelium of the labyrinthine sense organs. In the organ ofCorti, they were located mainly under the inner (IHC; fig. 7) and outer (OHC)hair cells (fig. 8). However, a small number was found among the nerve fibersin the osseous spiral lamina (fig. 9) and near the spiral ganglion in Rosenthal’scanal (fig. 10). In the vestibular labyrinth, these concretions were usuallylocated on the slopes of the cristae (fig. 11) and throughout the maculae (fig. 12).A small number of deposits was found in the ampullary, saccular and utricularnerve bundles near the end organs (fig. 13).

The concretions usually stained deep blue, but many in the organ of Cortiwere light blue in color and surrounded by a limiting membrane (fig. 14). Someof the larger concretions under OHC had a laminated appearance (fig. 8). Theconcretions in the vestibular organs were invariably dark blue in color (fig. 15).

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Fig. 7. The organ of Corti in case 2 (table 1, Appendix) shows a large concretion (openarrow) under the IHC (i). OHC (o) are present.

Deposits in the stria vascularis (fig. 16) and spiral prominence (fig. 17) were ofvariable size and a dark blue color. They did not follow any specific pattern ofdistribution.

The location of concretions in the TB of VN (n � 20), MD (n � 10) and BPV(n � 3) is summarized in tables 1–3 (Appendix). Concretions were found in thelabyrinthine sense organs or their nerve branches in all except 1 TB (table 3).Eleven of the 20 VN TB contained deposits in both vestibular and auditory endorgans, while 6 revealed them in vestibular organs only and 3 only in the organ


Fig. 8. There are 2 concretions (open arrows) under OHC in the organ of Corti in case 1(table 1, Appendix).

Fig. 9. a Two concretions (open arrow) are shown near the habenula perforata in theosseous spiral lamina of case 4 (table 1, Appendix). b A higher magnification of the depositsshown in a demonstrates the laminated structure.

of Corti. Four of the MD TB contained concretions in both vestibular and audi-tory sense organs and 6 only in the vestibular organs. Of the 2 BPV TB withconcretions, 1 contained them in both vestibular and auditory sense organswhile the other revealed only vestibular organ deposits.

The 33 TB in tables 1–3 contained 133 concretions (44 in the cochlea; 89in the vestibular organs) in the labyrinthine sense organs. The distribution ofthese deposits was plotted on a cochleogram and vestibulogram (fig. 18).Cochlear end organ deposits were concentrated in the upper basal turn with adiminishing frequency toward the apical and lower basal turns. In the vestibularsense organs, the deposits were located mostly along the slopes of the cristaeand in all areas of the maculae.

Deposits were found in the stria vascularis of 3 TB and in the spiral prominence of 1 TB from the VN group. Two MD TB contained concretions inthe stria vascularis and 2 in the spiral prominence. No deposits were found inthe stria vascularis or spiral prominence of the 3 BPV TB.

The VCA was examined at its takeoff from the saccular ganglion. It wasfound to be totally (n � 1) or partially (n � 15) degenerated in 16 of the VN TBand normal in 1 TB. The anastomosis was not available in 3 VN TB because ofavulsion of the eighth nerve in the internal auditory canal. In 9 TB with MD, theVCA was totally (n � 1) and partially (n � 8) degenerated but intact in 1. TheVCA was partially degenerated in all 3 TB with BPV.

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Fig. 10. A concretion (open arrow)can be seen in Rosenthal’s canal where the intraganglionic course of efferent fibersis adjacent to spiral ganglion cells (SG). ST � Scala tympani. Case 7, table 2(Appendix).


Fig. 11. Two concretions (open arrows) are shown in the neuroepithelium of the posteriorcanal crista. Case 3, table 2 (Appendix).

Fig. 12. Typical location for a concretion (open arrow) in the saccular macula. Case 3,table 2 (Appendix).

The 20 control TB were selected on the basis of absence of vestibular ganglion degeneration and a history of vertigo. These TB represent patients withage, sex and occupational demographics similar to those in the VN, MD andBPV groups. Several of these control TB contained concretions in sense organs:2 in both vestibular and auditory end organs, 4 in only vestibular sense organs,

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Fig. 13. Large concretion in the utricular nerve (open arrow) with a small artifactual(a) deposit. Case 10, table 2 (Appendix).

Fig. 14. A small light blue deposit (open arrow) near the base of OHC in the organ ofCorti. Case 1, table 1 (Appendix).


Fig. 15. A concretion (open arrow) in the neuroepithelium (*) of the utricular macula.Case 7, table 2 (Appendix).

Fig. 16. Two large deposits (open arrow) in the stria vascularis. Case 1, table 2(Appendix).

1 in the organ of Corti and 1 in the osseous spiral lamina. The control TB con-tained 14 deposits in the end organs (6 in cochlear; 8 in vestibular organs). Theseconcretions were plotted on a cochleogram and vestibulogram (fig. 19). Thecochlear end organ deposits were located in the upper basal and middle turns,while the vestibular deposits were distributed over the sense organ epithelium.

Five control TB revealed six concretions in the stria vascularis and 2 contained deposits in the spiral prominence. These strial deposits were ran-domly located along the cochlear duct. Two spiral prominence deposits in thevestibulopathic and 2 in the control TB were located in the upper basal turn. TheVCA was normal in 15 control TB, degenerated in 3 and not available (nerveavulsion) in 2 TB.

Discussion

The validity of deposits in the TB from VN, MD and BPV is supported byseveral bodies of evidence.

(1) The concretions were based on criteria which differentiate them fromartifacts of staining. The spherical and solid nature (sometimes laminated) with

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Fig. 17. Two small deposits in the spiral prominence region are indicated by an openarrow. Case 1, table 2 (Appendix).

a limiting border are primary criteria for the blue-colored concretions. Bluedroplets of the stain sometimes found in TB sections are smaller and semi-translucent when viewed at high power under the light microscope. The depositswere typically located between supporting and hair cells in the sense organ orbetween nerve bundles leading to the sensory epithelium.


a

Concretions – VN, MD, BPV TB

Cochleogram

G G

VN

MD

BPV

Osseous spirallamina

Spiral prominence

Pillarhead

Striavascularis

b

Vestibulogram

Utricle Saccule Posteriorcanal

Lateralcanal

Superiorcanal

Fig. 18. The spatial localization of concretions in the 33 vestibulopathic TB is represented on a cochleogram (a) and a vestibulogram (b). G � spiral ganglion.

(2) The majority of concretions were located along neural pathways or withinthe neurosensory epithelium of labyrinthine sense organs. Deposits in the striavascularis and spiral prominence were found with equal frequency and random-ness in the control and the vestibulopathic TB. These have been thought to berelated to degenerative effects from renal and cardiovascular disease [8–11].

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a

Concretions – Control TBCochleogram

b

Vestibulogram

Saccule Posteriorcanal

Lateralcanal

Superiorcanal

Fig. 19. The spatial localization of concretions in 20 control TB is shown in thiscochleogram (a) and vestibulogram (b).

(3) Dark bodies below the IHC and OHC of the organ of Corti in a patientwith long-standing sensorineural hearing loss were described in transmissionelectron microscopy of TB by Nadol [12]. These structures in the region underOHC were filled with either dark or light vesicles resulting in dark- and light-appearing bodies within a limiting membrane. Bud-like profiles under IHCfilled with mitochondria were also described. Spoendlin and Suter [13] regardedthese bud-like bodies as regenerating efferent axons several months after theeighth nerve had been transected in cats. Nadol’s patient had experienced suddenprofound deafness early in life and his TB revealed endolymphatic hydrops in all turns of the cochlea. Although the subject gave no history of vertigo, it ispossible that the TB findings represented delayed endolymphatic hydrops, avariant of MD.

(4) A comparison of the 133 concretions in 33 vestibulopathic TB with 14deposits in 20 control TB indicates a higher occurrence in the TB with focalaxonal degeneration of the vestibular ganglion. The small number of concretionsin the auditory (n � 6) and vestibular (n � 8) organs found in 20 TB withoutvestibular ganglion degeneration may suggest a subclinical form of vestibularganglionitis in patients without vestibular symptoms.

Although the distribution of concretions in the labyrinthine sense organsfollows neural pathways, it is probable that they are associated with the efferentrather than the afferent neuron. A greater number of deposits was found underthe OHC than under IHC, and the concretions under IHC were much larger thanthose under OHC. These features parallel the efferent innervation pattern in theorgan of Corti (see chapter 2). Furthermore, the concentration of organ of Corticoncretions is greatest in the upper basal turn with decreasing frequency towardthe apex and similarly the lower basal turn. The distribution of efferent terminalsis similar to that displayed by histochemical techniques [4].

The arrangement of concretions in vestibular organs also suggests deposi-tion in fibers of the efferent system [4, 14, 15]. Most deposits were found on the slopes of the cristae and in all regions of the maculae. A smaller number ofdeposits was seen at the crest of the cristae.

Arguments exist against an afferent neural location of the concretions.Since 95% of the afferent innervation to the auditory sense organ terminates onIHC [5, 16], the majority of deposits would be expected under IHC rather thanOHC if they represent afferent fibers. Moreover, type 1 cochlear neurons do notregenerate after injury. Type 1 spiral ganglion cells do not contact OHC wheremost of the concretions were located [16]. OHC are supplied by type 2 spiralganglion cells which survive destruction of their dendrite or axon [3, 5]. More-over, the innervation of OHC by type 2 ganglion cells is greatest at the apicalturn with diminishing frequency toward the base of the cochlea.


The location of the concretions near terminal portions of the efferent systemmay reflect an attempt at regeneration of axons interrupted by pathology in the vestibular ganglion where they are anatomically intimate with ganglion cellsand their satellite cells. Evidence of a degenerated OCB in the VCA was presentin 28 out of 33 vestibulopathic TB and in only 3 of 20 control TB. The occurrenceof concretions in the organ of Corti was proportionate to the number of TB witha degenerated VCA. Since efferent neurons have a vigorous regenerative capac-ity following eighth-nerve transection [13], deposits within sense organs andnerve branches may represent structures similar to growth cones in regeneratingperipheral nerve.

The presence of concretions in nerve branches to the end organs (osseousspiral lamina, Rosenthal’s canal, vestibular nerve branches) suggest regenerat-ing efferent axons which have turned back on themselves before reaching theend organ epithelium. Two deposits were found near the spiral ganglion (fig. 10)in the location of the intraganglionic spiral course of the OCB. This type ofregenerating nerve fiber was described by Spoendlin and Suter [13] proximal to the habenula perforata several months after eighth-nerve transection in cats.The presence of deposits in the vestibular nerve branches also suggests turnedback regenerating axons. The greater incidence of deposits in preterminal ratherthan proximal nerve branch segments supports the phenomenon of regeneratingefferent axons doubling back after meeting resistance near the basement mem-brane of the neurosensory epithelium. The number of concretions detected by light microscopy is probably an underestimate of their actual number inhuman TB. Examination of these TB by transmission electron microscopy couldreveal a larger number of sub-light-microscopic profiles characteristic of neuralregeneration.

Since new information on auditory and vestibular physiology is available,the clinical effects of efferent system paralysis should be considered. It has longbeen known that the OCB exerts an inhibitory effect on sound-provoked eighth-nerve action potentials [17, 18]. Since the demonstration that the sensitivity(tuning) of auditory units is provided by a normal OHC system, a cochlear ampli-fier function by OHC has been assumed [19, 20]. The OHC exert a mechanicaleffect on cochlear partition mechanics [21, 22] and thus give rise to energyreleased as otoacoustic emissions (OAE) in the ear canal [23]. Inhibitory actionon OHC contractibility by an intact OCB normally provides a regulatory controlover this amplifier system [19, 20]. When the OCB has been transected (i.e. vestibular nerve transection), OAE are increased and resist reduction bycontralateral sound stimulation [24, 25]. Although the frequencies of tinnitusand spontaneous OAE do not match in most subjects when this has been studied,there have been reports of a precise match of OAE with the tinnitus [26].Furthermore, increased spontaneous OAE have been reported in patients with

Gacek 120

MD [27], and relief of tinnitus has been achieved by intratympanic applicationof anti-inflammatory [28] or cholinergic drugs [29]. By the reduction of inflam-mation and reinstitution of efferent neural transmission, a beneficial effect ontinnitus may be possible through the efferent system.

Vestibular efferent activity has been mostly inhibitory [30–34] when studiedexperimentally although some reports of an excitatory effect have appeared [35].The hypothesis of function with the most solid experimental and evolutionarysupport is that of an efferent feed-forward mechanism. Most of this evidence isprovided from studies of lateral line organs in fish [36–40]. In such a theory, the vestibular organs are subject to an efferent influence that adjusts for thestimuli affecting the sense organs during movement of the animal. It has beendemonstrated in the lateral line organ that efferents are activated before movementof the animal [36, 38]. By reducing the sensitivity of input from the sense organ,this activity prevents self-stimulation during vigorous swimming movements.By analogy to these experiments in fish, a common complaint in patients withVN, MD or BPV is that of motion intolerance with sudden head movement.

Based upon morphologic changes in the afferent and efferent labyrinthinepathways in TB from patients with VN, MD and BPV, two categories of dys-function (symptoms) seem possible. The primary pathology is a reactivatedlatent neurotropic viral vestibular ganglionitis which is responsible for episodicvertigo. Depending on the strain of virus (anterograde vs. retrograde), hearingloss may be absent (VN) or associated with vertigo (MD). A secondary pathol-ogy is the inflammatory paralysis or degeneration of efferent pathways to thelabyrinth. This effect occurs at the point where efferent axons pass through thevestibular (saccular) ganglion. Loss of efferent function may result in increasedOAE (auditory) which could give rise to tinnitus as well as motion intolerance(vestibular). It may be useful in the evaluation of patients with recurrentvestibulopathy to classify symptoms as ‘primary’ and ‘secondary’ depending onthe neural system affected by vestibular ganglionitis.

References

1 Rasmussen GL: The olivary peduncle and other fiber connections of the superior olivary complex.J Comp Neurol 1946;84:141–219.

2 Rasmussen GL: Further observations of the efferent cochlear bundle. J Comp Neurol 1953;99:61–74.

3 Spoendlin H, Gacek RR: Electron microscopic study of the efferent and afferent innervation of the organ of Corti in the cat. Ann Otol 1963;72:660–686.

4 Gacek RR, Nomura Y, Balogh K: Acetylcholinesterase activity in the efferent fibers of the stato-acoustic nerve. Acta Otolaryngol 1965;59:541–553.

5 Spoendlin H: The innervation of the organ of Corti. J Laryngol 1967;81:717–738.6 Gacek RR: Efferent component of the vestibular nerve; in Rasmussen GL, Windle WF (eds): Neural

Mechanisms of the Auditory and Vestibular Systems. Springfield, Thomas, 1960, pp 276–284.


7 Rollin H: Über Kalkablagerungen in der Stria vascularis des Labyrinthes. Arch Klin Exp OhrenNasen Kehlkopfheilkd 1934;138:1–5.

8 Friedmann I, Fraser GR, Froggatt P: Pathology of the ear in the cardio-auditory syndrome of Jervell and Lange-Nielsen (recessive deafness with electrocardiographic abnormalities). J Laryngol Otol 1966;80:451–470.

9 Naunton R, Lindsay J, Stein L: Concretions in the stria vascularis. Arch Otolaryngol 1973;97:376–380.

10 Oda M, Preciado MC, Quick CA, Paparella MM: Labyrinthine pathology of chronic renal failure patients treated with hemodialysis and kidney transplantation. Laryngoscope 1974;84:1489–1506.

11 Zaytoun GM: Basophilic deposits in the stria vascularis – A clinicopathologic update. Ann OtolRhinol Laryngol 1983;92:242–248.

12 Nadol JB: Electron microscopic observations in a case of long-standing profound sensorineuralhearing loss. Ann Otol Rhinol Laryngol 1977;86:507–517.

13 Spoendlin HH, Suter P: Regeneration in the VIII nerve. Acta Otolaryngol 1976;81:228–238.14 Gacek RR: Anatomical evidence for an efferent vestibular pathway. 3rd Symp Role Vestibular

Organs Space Exploration, NASA, Pensacola, FL., 1967, pp 203–212.15 Spoendlin H: Ultrastructural studies of the labyrinth in squirrel monkeys. 1st Symp Role

Vestibular Organs Space Exploration, NASA, Pensacola, FL., 1965, pp 7–22.16 Spoendlin H: Innervation patterns in the organ of Corti of the cat. Acta Otolaryngol 1969;

67:239–254.17 Galambos R: Suppression of auditory nerve activity by stimulation of efferent fibers to the

cochlea. J Neurophysiol 1956;19:424–437.18 Fex J: Auditory activity in centrifugal and centripetal cochlear fibers in cat. Acta Physiol Scand

1962;189(suppl):1–68.19 Zenner HP, Reuter G, Plinkert PK, Zimmerman U, Glitter AH: Outer hair cells possess acetyl-

choline receptors and produce motile responses in the organ of Corti; in Wilson JP, Kemp DT(eds): Cochlear Mechanisms. London, Plenum Press, 1989, pp 93–98.

20 Dallos P, Evans BN, Hallworth R: Nature of the motor element in electrokinetic shape changes ofcochlear outer hair cells. Nature 1991;350:155–157.

21 Reuter G, Zenner HP: Active radial and transverse motile responses of outer hair cells in the organof Corti. Hear Res 1990;43:219–230.

22 Brownell WE: Outer hair cell electromotility and otoacoustic emissions. Ear Hear 1990;11:82–92.23 Kemp DT: Stimulated acoustic emissions from within the human auditory system. J Acoust Soc

Am 1978;64:1386–1391.24 Williams EA, Brookes GB, Prasher DK: Effects of contralateral acoustic stimulation on oto-

acoustic emissions following vestibular neurectomy. Scand Audiol 1993;22:197–203.25 Williams EA, Brookes GB, Prasher DK: Effects of olivocochlear bundle section on otoacoustic

emissions in humans: Efferent effects in comparison with control subjects. Acta Otolaryngol(Stockh) 1994;114:121–129.

26 Plinkert PK, Gitter AH, Zenner HP: Tinnitus associated spontaneous otoacoustic emissions. ActaOtolaryngol (Stockh) 1990;110:342–347.

27 Haginomori S, Makimoto K, Tanaka H, Araki M, Takenaka H: Spontaneous otoacoustic emissionsin human with endolymphatic hydrops. Laryngoscope 2001;111:96–101.

28 Shulman A, Goldstein B: Intratympanic drug therapy with steroids for tinnitus control: A preliminaryreport. Int Tinnitus J 2000;6:10–20.

29 DeLucchi E: Transtympanic pilocarpine in tinnitus. Int Tinnitus J 2000;6:37–40.30 Sala O: Vestibular efferent system: Electrophysiological research. Acta Otolaryngol 1965;

59:329–337.31 Llinas R, Precht W: The inhibitory vestibular efferent system and its relation to the cerebellum in

the frog. Exp Brain Res 1969;9:16–29.32 Dieringer N, Blanks RH, Precht W: Cat efferent vestibular system: Weak suppression of primary

afferent activity. Neurosci Lett 1977;5:285–290.

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33 Dechesne C, Sans A: Control of the vestibular nerve activity by the efferent system in the cat. ActaOtolaryngol 1980;90:82–85.

34 Russell IJ, Roberts BL: Inhibition of spontaneous lateral line activity by efferent nerve stimulation.J Exp Biol 1972;57:77–82.

35 Goldberg JM, Fernandez C: Efferent vestibular system in the squirrel monkey: Anatomical locationand influence on afferent activity. J Neurophysiol 1980;43:986–1026.

36 Klinke R, Galley N: Efferent influence on the vestibular organ during active movements of thebody. Arch Ges Physiol 1970;318:325–332.

37 Roberts BL, Russell IJ: Efferent activity in the lateral line nerve of dogfish. J Physiol (Lond) 1970;208:37.

38 Roberts BL, Russell IJ: The activity of lateral line efferent neurons in stationary and swimmingdogfish. J Exp Biol 1972;57:435–448.

39 Russell IJ, Roberts BL: Inhibition of spontaneous lateral line activity by efferent nerve stimulation.J Exp Biol 1972;57:77–82.

40 Flock A, Russell IJ: Inhibition by efferent nerve fibers: Action on hair cells and afferent synaptictransmission in the lateral line organ of the burbot Lota lota. J Physiol (Lond) 1976;257:45–62.



Antiviral Therapy of VestibularGanglionitis


The material presented in the preceding chapters suggests an antiviralapproach in the treatment of recurrent balance disorders caused by vestibularganglionitis. Attempts at treating vestibular neuronitis and Ménière’s diseasewith oral antiviral drugs have not been effective for several reasons. In additionto insensitivity of the virus strain to the current generation of antiviral drugs,some features of neurotropic virus biology represent barriers to virus neutral-ization by these chemical substances. The intranuclear location of latent virus inganglion cells offers a shield against antiviral drugs and circulating antibodies.Nucleic acids released by virus are only neutralized by nuclease enzymes inwhite blood cells. Antiviral drugs can be effective only when the virus is reacti-vated and released from the ganglion cell into the extracellular space. Eventhen, virus particles are offered some isolation by satellite cells of the ganglion.Finally, the blood-brain barrier limits the amount of antiviral drug that reachesthe neuron. Increasing the intake of antiviral drugs to overcome this barrier isrestricted by increasing undesirable side effects of drug ingestion. These featuresof neurotropic virus biology and of the current generation of antiviral drugs represent some reasons for the failure of orally administered antiviral drugs inthe treatment of recurrent vestibulopathies.

As discussed in chapter 8, it is useful in these vestibulopathies to recognizesymptoms that result from an intracellular (intraganglionic) location of the virusand those that are produced by the extraganglionic effect of the viral organism.We might refer to these as primary and secondary symptoms.

Primary symptoms of vestibular ganglionitis are produced by the viraleffect on the physiology of the ganglion cell in the eighth nerve. The precisemechanism by which a disturbance in cell physiology results from reactivationof the virus is unknown. It may have something to do with disruption of the ionicgradient across the cell and/or nuclear membrane. The symptoms and signs

Chapter 9

caused by virus in this location are vertigo and/or hearing loss if the virus alsoreaches a spiral ganglion location.

Secondary symptoms are produced by release of the reactivated virus or itsnucleic acids through the ganglion cell membrane into the extracellular space.In the extracellular space, the toxic proteins and/or nucleic acids are taken up byan increased number of satellite cells. These satellite cells are related to and incontinuity with Schwann cells of nearby neuronal fiber pathways. Passing neuralsystems closely located to the vestibular ganglion are the efferent pathways tothe vestibular and auditory sense organs. Paralysis of function and degenerationof efferent axons may result from extraganglionic spread of infection within the vestibular ganglion. Chapter 8 defined a possible symptom arising fromdysfunction of the efferent auditory bundle as tinnitus produced by enhancedotoacoustic emissions which result from a lack of olivocochlear bundle inhibitoryfunction on outer hair cells in the organ of Corti. In the vestibular system, lossof an inhibitory efferent effect on vestibular sense organs may lead to disequi-librium caused by activity in the sense organs caused by self-stimulation.

The loss of an efferent system effect may be reversible if the paralysis ofefferents is only physiologic. The loss would be irreversible if the inflammatoryeffect on efferent fibers resulted in degeneration of the efferent pathways. Sincethe toxic effect on efferent pathways is extraganglionic in location, it can bereached by antiviral drugs delivered into the extracellular compartment (plasma).

The following are some comments formed after a year of using antiviraldrugs to treat vestibular neuronitis and Ménière’s disease.

(1) Oral antivirals such as acyclovir and valacyclovir mediate their effectby interference in the thymidine kinase enzyme systems necessary for virusreplication. The administration of acyclovir in a dose of 800 mg three times aday for a 3-week period, or valacyclovir 1 g three times a day for 3 weeks, is astarting point for the oral administration of antiviral drugs in recurrent ves-tibulopathies. If a beneficial effect is observed within the 3-week period, it isrepeated for a second 3-week course to a total of 6 weeks as the initial treatmentfor recurrent vestibular ganglionitis.

(2) If the oral administration of the antiviral drug is unsuccessful as evidenced by lack of relief in primary symptoms, if its side effects (gastroin-testinal) prevent its use or if a higher dose of the antiviral drug is desired,intratympanic administration of the antiviral compound for diffusion throughthe round window membrane into the perilymphatic compartment is a reason-able next step. Since ganciclovir (Cytovene) is the only antiviral drug approvedfor intraorgan use, this has been selected for intratympanic antiviral administra-tion in balance disorders. The antiviral agent is administered over a microwickwhich is inserted through a subannular tunnel into the round window nicheunder local anesthesia. The antiviral substance is applied daily on the wick for

Antiviral Therapy of Vestibular Ganglionitis 125

Gacek/Gacek 126

5 days, following which the wick is removed from the ear canal. Some relief ofprimary but more of secondary symptoms has been obtained using this method.However, ganciclovir has an irritative effect on the soft tissues of the ear canaland the tympanic membrane, leading to discomfort in the ear being treated insome patients.

(3) Intralabyrinthine implantation of ganciclovir has been considered butnot yet employed. The ganciclovir implant may be placed within the perilym-phatic compartment, preferably of the pars superior, but would require a surgicalprocedure such as simple mastoidectomy and fenestration of the bony labyrinthfor placement of the implant. Such an application of an antiviral drug is experi-mental and should not be employed in a hearing ear.

In consideration of the antimicrobial approach, it must be realized thatthere may be a virus effect through nucleic acid release. Therefore it may benecessary to design nuclease pharmaceuticals for use in the neutralization oftoxic viral products. Further research is necessary to design and produce newantiviral or nuclease substances for the treatment of recurrent vestibulopathies.


Abbreviations for Tables 1–4

MG � Meatal ganglionVG � Vestibular ganglionSG � Spiral ganglionTN � Tympanic nerveOCB � Olivocochlear bundleOSL � Osseous spiral laminaSV � Stria vascularisSP � Spiral prominenceEH � Endolymphatic hydropsVest. fib. � Vestibular cistern fibrosisOutpouch. � Outpouching (pars superior)PC � Posterior canal cristaLC � Lateral canal cristaSC � Superior canal cristaAGL � Apical ganglion lossMI � Myocardial infarctionSNHL � Sensorinerual hearing lossCVA � Cerebrovascular accidentBPV � Benign paroxysmal positional

vertigo

* � History of vertigoAT � Apical turnBT � Basal turnVR � Vestibular responseNA � Not availableN � NormalD � DegeneratedOC � Organ of CortiIHC � Inner hair cellOHC � Outer hair cellU � Utricular maculaS � Saccular maculaSOM � Secous otitis mediaGI � GastrointestinalCOM � Chronic otitis mediaGM � GramTM � Tympanic membraneFigures after abbreviations indicateIndicate number of concretions.

Appendix

Tabl

e 1.

His

topa

thol

ogy

of te

mpo

ral b

ones

: ves

tibu

lar

neur

onit

is

Age

/O

tolo

gic

Cau

se o

fD

egen

erat

ion

Con

cret

ions

sex

diag

nosi

sde

ath

MG

VG

SG

TN

OC

Ben

d or

gan

OS

LS

VS

P

159

/MN

eura

l pre

sbyc

usis

Met

asta

tic

carc

inom

a13

%�

10%

AT

DD

OC

-7 O

HC

00

0N

oise

dea

fnes

sth

yroi

d 50

%L

C-2

267

/MS

tim

ulat

ion

deaf

ness

Rup

ture

d ao

rtic

20%

15%

NN

DO

C-2

IH

C0

10

aneu

rysm

S-3

362

/M*

Men

ingi

oma

SO

MM

enin

giom

a3%

�10

%N

NN

PC

-10

00

mid

dle

and

post

erio

r fo

ssa

487

/FN

eom

ycin

toxi

city

Pne

umon

ia11

%10

%B

TD

D0

30

030

%

544

/M*

Hem

olab

yrin

thS

ubar

achn

oid

23%

�10

%N

DD

U-1

00

0he

mor

rhag

eS

-1

652

/M*

Unk

now

nM

I10

%30

%N

ND

U-2

12

0ve

stib

ulop

athy

S-1

787

/F*

Ves

tibu

lar

neur

onit

isM

I

2%40

%B

TN

DO

C-6

OH

C0

00

Mul

tisy

stem

em

boli

smV

R-0

50%

PC

-4

868

/F*

Pre

sbyc

usis

Pul

mon

ary

embo

lus

12%

40%

NN

NA

U-1

00

0S

tria

l atr

ophy

971

/M*

Atr

ophy

SV

and

B

rain

stem

infa

rcti

on22

%40

%A

T

DD

U-1

01

0sp

iral

liga

men

tC

arci

nom

a pr

osta

teV

R ⇓

seve

ral

Appendix 128

Appendix 129

1092

/F*

Ves

tibu

lar

neur

onit

isA

ther

oscl

eros

is6%

10%

AT

NN

AL

C-1

10

0A

trop

hy S

V a

nd

VR

-0se

vera

lU

-1or

gan

of C

orti

S-4

PC

-2

1167

/MS

tim

ulat

ion

deaf

ness

Car

diac

fai

lure

20%

�15

%N

NN

AO

C-2

OH

C0

00

Vir

al la

byri

nthi

tis

OC

-1 I

HC

U-1

1258

/M*

Atr

ophy

org

an o

f C

orti

,H

yper

tens

ion

wit

h 8%

40%

BT

ND

OC

-2 I

HC

00

0S

V a

nd S

P g

angl

ion

cere

bral

hem

orrh

age

VR

-050

%U

-1S

-1

1373

/FP

resb

ycus

isP

neum

onia

15%

30%

NN

DO

C-1

IH

C0

00

Str

ial a

trop

hyO

C-1

OH

C

1469

/FO

tosc

lero

sis

Bre

ast c

ance

r w

ith

5%30

%B

TN

DO

C-1

IH

C0

00

met

asta

ses

50%

U-1

Pne

umon

iaS

-1

1581

/FS

tria

l atr

ophy

MI

8%�

10%

AT

ND

OC

-1 I

HC

00

0N

eura

l pre

sbyc

usis

Hea

rt f

ailu

re50

%O

C-1

OH

CS

-2P

C-1

1681

/M*

Oto

scle

rosi

sC

ardi

ac a

rres

t40

%�

10%

BT

DD

OC

-2 O

HC

00

1(l

eft)

40%

U-1

S-1

1781

/M*

Oto

scle

rosi

sC

ardi

ac a

rres

t0

10%

BT

ND

OC

-2 O

HC

00

0(r

ight

)30

%U

-1

1880

/MN

eura

l pre

sbyc

usis

Leu

kem

ia16

%�

10%

AT

DD

OC

-1 O

HC

00

0A

cous

tic

trau

ma

GI

blee

d50

%O

C-1

IH

C

Appendix 130

Tabl

e 1.

(con

tinu

ed)

Age

/O

tolo

gic

Cau

se o

fD

egen

erat

ion

Con

cret

ions

sex

diag

nosi

sde

ath

MG

VG

SG

TN

OC

Ben

d or

gan

OS

LS

VS

P

1962

/MN

eura

l pre

sbyc

usis

Unk

now

n8%

�10

%B

TD

DS

-10

00

Inac

tivat

ed C

OM

30%

U-4

2070

/M*

SN

HL

Bra

inst

em in

farc

tion

1%�

10%

ND

DL

C-2

00

0S

tria

l atr

ophy

S

-2V

erti

goP

C-2

Appendix 131

Tabl

e 2.

His

topa

thol

ogy

of te

mpo

ral b

ones

: Mén

ière

’s d

isea

se

Age

/O

tolo

gic

Cau

se o

fD

egen

erat

ion

Con

cret

ions

Oth

erse

xdi

agno

sis

deat

hfi

ndin

gs

MG

VG

SG

TN

OC

Ben

d or

gan

OS

LS

VS

P

183

/F*

Mén

ière

’s d

isea

seR

espi

rato

ry f

ailu

re7%

�10

%A

TN

NU

-20

21

EH

Ova

rian

car

cino

ma

50%

S-2

AG

L

271

/F*

Mén

ière

’s d

isea

seB

rain

infa

rcti

on17

%20

%B

TN

DO

C-2

OH

C1

(SG

)0

0V

est.

fib.

30%

PC

-4E

H

358

/M*

Mén

ière

’s d

isea

seC

VA

8%�

5%N

ND

S-1

00

0E

H(l

eft)

Pne

umon

iaP

C-4

OC

-2 O

HC

458

/M*

Mén

ière

’s d

isea

seC

VA

7%�

15%

ND

DS

-10

00

Ves

t. fi

b.(r

ight

)P

neum

onia

PC

-1E

H

583

/F*

Mén

ière

’s d

isea

seL

euke

mia

16%

�10

%B

TN

DL

C-1

00

0V

est.

fib.

(lef

t)30

%O

utpo

uch.

AT

EH

30%

AG

L

683

/F*

Mén

ière

’s d

isea

seL

euke

mia

20%

10%

BT

ND

U-2

00

0V

est.

fib.

(rig

ht)

20%

EH

778

/M*

Mén

ière

’s d

isea

seC

ardi

ac a

rres

t0

�10

%B

TN

DU

-11

(SG

)0

0E

H(l

eft)

30%

S-1

Out

pouc

h.A

TS

C-5

AG

L50

%O

C-1

IH

CO

C-1

OH

C

Appendix 132

Tabl

e 2.

(con

tinu

ed)

Age

/O

tolo

gic

Cau

se o

fD

egen

erat

ion

Con

cret

ions

Oth

erse

xdi

agno

sis

deat

hfi

ndin

gs

MG

VG

SG

TN

OC

Ben

d or

gan

OS

LS

VS

P

878

/M*

Mén

ière

’s d

isea

seC

ardi

ac a

rres

t20

%10

%B

TN

DU

-20

00

EH

(rig

ht)

30%

976

/F*

Mén

ière

’s d

isea

seC

ereb

ral

24%

15%

BT

DD

U-1

01

0V

est.

fib.

hem

orrh

age

75%

LC

-1E

HO

utpo

uch.

1065

/F*

Mén

ière

’s d

isea

seC

ereb

ral

30%

40%

BT

ND

U-2

00

0V

est.

fib.

hem

orrh

age

30%

S-2

EH

OC

-1 O

HC

Appendix 133

Tabl

e 3.

His

topa

thol

ogy

of te

mpo

ral b

ones

: ben

ign

paro

xysm

al p

osit

iona

l ver

tigo

Age

/O

tolo

gic

Cau

se o

fD

egen

erat

ion

Con

cret

ions

sex

diag

nosi

sde

ath

MG

VG

SG

TN

OC

Ben

d or

gan

OS

LS

VS

P

175

/F*

BP

VR

espi

rato

ry a

nd c

ardi

ac4%

�15

%B

TN

D0

00

0fa

ilur

e(i

nfer

ior)

50%

265

/M*

BP

VP

ulm

onar

y tu

berc

ulos

is17

%�

15%

BT

DD

U-2

00

0(i

nfer

ior)

10%

391

/F*

BP

VC

ereb

ral i

nfar

ctio

n10

%�

15%

BT

ND

OC

-1 I

HC

00

0(i

nfer

ior)

50%

S-1

PC

-3L

C-4

Appendix 134

Tabl

e 4.

His

topa

thol

ogy

of c

ontr

ol te

mpo

ral b

ones

Age

/O

tolo

gic

diag

nosi

sC

ause

of

deat

hD

egen

erat

ion

Con

cret

ions

sex

MG

VG

SG

TN

OC

Ben

d or

gan

OS

LS

VS

P

184

/MO

tosc

lero

sis

MI

00

BT

NN

OC

-2 O

HC

00

130

%

221

/MT

B f

ract

ure

Hea

d in

jury

Lac

erat

ion

liver

, 0

0B

TD

NA

00

00

sple

en, a

orta

50%

381

/MO

tosc

lero

sis

Inte

stin

al0

0B

TN

N0

00

0L

eft s

tape

dect

omy

infa

rcti

on50

%

459

/MF

uros

emid

e Fo

llic

ular

00

BT

ND

OC

-2 I

HC

10

0ot

otox

icit

yly

mph

oma

20%

PC

-1

586

/MP

resb

ycus

isG

M (

–) s

epsi

s0

0B

TN

N0

00

0(r

ight

)30

%

687

/FP

resb

ycus

isH

eart

fai

lure

00

BT

NN

00

00

30%

782

/FO

tosc

lero

sis

MI

00

ND

N0

00

0(r

ight

)M

alle

us f

ixat

ion

877

/FS

NH

LM

I0

0B

TN

NS

-10

10

TM

per

fora

tion

50%

Appendix 135

99/

ML

abyr

inth

ine

Leu

kem

ia0

0N

NN

00

00

hem

orrh

age

1091

/MP

resb

ycus

isM

I P

ulm

onar

y0

0B

TN

N0

00

1em

boli

sm15

%

1180

/FS

tria

l atr

ophy

GI

hem

orrh

age

00

BT

DN

00

00

Neu

ral p

resb

ycus

is30

%

1276

/MN

eura

l pre

sbyc

usis

MI

Pul

mon

ary

00

BT

NN

00

00

Str

ial a

trop

hyed

ema

50%

1338

/MU

sher

’s s

yndr

ome

Liv

er f

ailu

re0

0B

TN

N0

00

0Pe

rito

niti

s70

%

1491

/FC

ontr

alat

eral

BP

VC

ereb

ral

00

BT

NN

PC

-20

20

(lef

t)in

farc

tion

50%

1569

/MH

emol

abyr

inth

Met

asta

tic

00

BT

NN

A0

00

0ca

rcin

oma

50

%P

rost

ate

pn

eum

onia

1676

/FC

hron

ic o

titi

s m

edia

Cer

ebra

l0

050

%D

DS

-10

10

and

laby

rint

hiti

she

mor

rhag

e

1786

/MP

resb

ycus

isG

M (

–)9%

0B

TN

NO

C-1

IH

C0

10

(lef

t)se

psis

30%

S-1

PC

-1

1882

/FO

tosc

lero

sis

MI

00

NN

N0

00

0(l

eft)

Appendix 136

Tabl

e 4.

(con

tinu

ed)

Age

/O

tolo

gic

diag

nosi

sC

ause

of

deat

hD

egen

erat

ion

Con

cret

ions

sex

MG

VG

SG

TN

OC

Ben

d or

gan

OS

LS

VS

P

1954

/FS

ubar

achn

oid

Cer

ebra

l0

0B

TN

N0

00

0he

mor

rhag

ehe

mor

rhag

e50

%N

eom

ycin

toxi

city

(coc

hlea

r)

2047

/MN

oise

dea

fnes

sP

neum

onia

00

NN

DP

C-1

01

0M

itra

l ste

nosi

s

137

Subject Index

Acyclovir, vestibular ganglionitis treatment125

Antiviral therapy, vestibular ganglionitis125, 126

Bell’s palsyetiology 32, 46geniculate ganglion role 32, 33, 38,

41–44, 46herpes simplex virus role 46, 51magnetic resonance imaging studies 33,

34, 36, 48–51meatal ganglion role 32, 33, 38, 41–44,

48susceptibility of individuals 51temporal bone studies

cranial nerve morphological changes36, 37, 46, 48

histopathology 37, 38, 41–44Benign paroxysmal positional vertigo

classification of recurrentvestibulopathies 102, 103

clinical features 80, 81, 85, 86clinical series for classification 94,

96–99comorbidity with vestibular disease 87,

100, 101neurotropic virus reactivation role 86temporal bone studies

histopathology 82, 84–86, 92, 93, 133overview 81specimens 81, 82

treatment 80

Cochlear nerve, anatomy 19, 24, 25, 27Cranial nerve

V, see Trigeminal nerveVIII

cochlear nerve 19, 24, 25, 27efferent vestibular pathway 22, 23hair cell afferent neurons 20, 21vestibular nerve 19–22

IX, see Glossopharyngeal nerveneurotropic virus sensitivity 12

Efferent system, degeneration in vestibularganglionitisanatomy 105primary vs secondary pathology 121temporal bone studies

concretions 109–112, 116, 117, 119

controls 114, 116electron microscopy 118, 120light microscopy 106specimens 106

Endolymphatic hydrops, Ménière disease67, 70, 71, 74–76

Facial nerve, see also Bell’s palsyanatomy 14–19brainstem nuclei origins 15, 16functional neuron groups 14, 15geniculate ganglion 15, 18, 19magnetic resonance imaging in Bell’s

palsy 33, 34, 36, 48–51meatal ganglion 15, 18, 19, 21

Subject Index 138

Ganciclovir, vestibular ganglionitistreatment 125, 126

Ganglion cell, neurotropic virus infection 7Geniculate ganglion

Bell’s palsy role 32, 33, 38, 41–44, 46facial nerve 15, 18, 19temporal bone content 32

Glossopharyngeal nerve, anatomy 27, 29

Hematoxylin, staining 9Herpes simplex virus

Bell’s palsy role 46, 51cranial neuropathy association 8, 9diseases 1envelope glycoproteins 1, 2histological studies of infection 9incidence of exposure 1infection cycle 2, 3, 5latency 5Ménière disease role 68, 73receptors 2recurrent vestibulopathy role 100vestibular neuronitis role 63, 64

Idiopathic facial paralysis, see Bell’s palsyInner hair cell

concretions with hearing loss 119nerve termination 24, 27, 119

Magnetic resonance imagingBell’s palsy studies 33, 34, 36, 48–51Ménière disease studies 74, 96–99vestibular neuronitis studies 54, 63,

96–99Meatal ganglion

Bell’s palsy role 32, 33, 38, 41–44, 48facial nerve 15, 18, 19, 21, 99temporal bone content 32, 99vestibular neuronitis changes 55–57,

62–65, 99Ménière disease

animal models 76antiviral therapy 125, 126classification of recurrent

vestibulopathies 102, 103clinical features 67, 75–77clinical series for classification 94, 96–99

comorbidity with vestibular disease 87,100, 101

endolymphatic hydrops 67, 70, 71,74–76

etiology 67, 68, 75herpes simplex virus role 68, 73magnetic resonance imaging studies 74,

96–99sensorineural hearing loss 76, 77temporal bone studies

histopathology 69–71, 73, 93, 94,131, 132

specimen preparation 68, 69vestibular ganglion changes 69, 71, 74

Neurotropic virus, see also specific virusescranial nerve sensitivity 12�-herpesviruses 1infection cycle 2, 3, 5nucleic acid infectivity 8recurrent vestibulopathy role 89, 99–102

Olivocochlear bundleanatomy 25, 27efferent system paralysis 120

Otalgia, recurrent vertigo association 101Outer hair cell

concretions with hearing loss 119nerve termination 24, 27, 119

Recurrent vestibulopathyclassification

case reports 90–94clinical series 94, 96–99temporal bone specimen review 89–94

neurotropic virus role 89, 99–102

Satellite cellbenign paroxysmal positional vertigo

changes 82neurotropic virus infection 2, 3, 5, 7, 100

Temporal boneBell’s palsy studies

cranial nerve morphological changes36, 37, 46, 48

histopathology 37, 38, 41–44

Subject Index 139

benign paroxysmal positional vertigostudieshistopathology 82, 84–86, 92, 93, 133overview 81specimens 81, 82

control bone histopathology 134–136efferent system degeneration in

ganglionitisconcretions 109–112, 116, 117, 119controls 114, 116electron microscopy 118, 120light microscopy 106specimens 106

Ménière disease studieshistopathology 69–71, 73, 93, 94,

131, 132specimen preparation 68, 69

vestibular neuronitis studieshistopathologic findings 56, 57, 60–63,

90, 128–130specimen assessment 55, 56

Trigeminal nerve, anatomy 12, 13Tympanic nerve, degeneration with

vestibulopathies 101, 102

Valacyclovir, vestibular ganglionitistreatment 125

Vestibular ganglionitis, efferent systemdegenerationanatomy 105

antiviral treatment 125, 126primary vs secondary pathology 121symptoms, primary vs secondary 124,

125temporal bone studies

concretions 109–112, 116, 117, 119controls 114, 116electron microscopy 118, 120light microscopy 106specimens 106

Vestibular nerveanatomy 19–22, 105Ménière disease, vestibular ganglion

changes 69, 71, 74neuronitis

antiviral therapy 125, 126clinical features 54, 55, 64, 65clinical series for classification 94,

96–99degeneration of nerve 54, 55, 62–65herpes simplex virus role 63, 64magnetic resonance imaging studies

54, 63, 96–99meatal ganglion changes 55–57, 62–65temporal bone studies

histopathologic findings 56, 57,60–63, 90, 128–130

specimen assessment 55, 56vestibular ganglion changes 55, 57,

61–65

viral neuropathies

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